chr12-120999579-A-G

Variant names:

• chr12-120999579-A-G
• rs1169305
• NM_000545.8:c.1720A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP5

This summary comes from the ClinGen Evidence Repository: The c.1720A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to glycine at codon 574 (p.(Ser574Gly)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.996; however, given that the G (Gly) alternate allele has frequencies ≥95% in all subpopulations, we have recalculated the Popmax Filtering allele frequency based on the highest prevalence of the A (Ser) reference allele being found in the African/African-American subpopulation (1144/24164 = 0.0473). The newly calculated Popmax Filtering allele frequency is 0.0447, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1720A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214285/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.99 (74262 hom., cov: 32)
  • Exomes 𝑓: 1.0 (728232 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign reviewed by expert panel P:3 B:8 O:2
• Conservation: PhyloP100: 0.738
• Publications: 65 publications found

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

HNF1A Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.1720A>G	p.Ser574Gly	missense	Exon 9 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1741A>G	p.Ser581Gly	missense	Exon 9 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.1528A>G	p.Ser510Gly	missense	Exon 8 of 9	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1720A>G	p.Ser574Gly	missense	Exon 9 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.1741A>G	p.Ser581Gly	missense	Exon 9 of 10	ENSP00000438804.1
	HNF1A	ENST00000540108.1	TSL:1	n.*1160A>G		non_coding_transcript_exon	Exon 8 of 9	ENSP00000445445.1

Frequencies

GnomAD3 genomes AF: 0.987 AC: 150280 AN: 152240 Hom.: 74204 Cov.: 32

Gnomad AFR AF: 0.955

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.996 AC: 242441 AN: 243302 AF XY: 0.997

Gnomad AFR exome AF: 0.952

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1458380 AN: 1460398 Hom.: 728232 Cov.: 56 AF XY: 0.999 AC XY: 725656 AN XY: 726522

African (AFR) AF: 0.953 AC: 31888 AN: 33474

American (AMR) AF: 0.997 AC: 44571 AN: 44692

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26106 AN: 26106

East Asian (EAS) AF: 1.00 AC: 39686 AN: 39692

South Asian (SAS) AF: 1.00 AC: 86215 AN: 86222

European-Finnish (FIN) AF: 1.00 AC: 52400 AN: 52400

Middle Eastern (MID) AF: 0.998 AC: 5662 AN: 5674

European-Non Finnish (NFE) AF: 1.00 AC: 1111687 AN: 1111818

Other (OTH) AF: 0.997 AC: 60165 AN: 60320

GnomAD4 genome AF: 0.987 AC: 150397 AN: 152358 Hom.: 74262 Cov.: 32 AF XY: 0.988 AC XY: 73612 AN XY: 74498

African (AFR) AF: 0.955 AC: 39725 AN: 41584

American (AMR) AF: 0.995 AC: 15242 AN: 15312

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68024 AN: 68036

Other (OTH) AF: 0.991 AC: 2094 AN: 2114

Alfa AF: 0.993 Hom.: 49032

Bravo AF: 0.985

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.962 AC: 4219

ESP6500EA AF: 1.00 AC: 8575

ExAC AF: 0.996 AC: 120540

Asia WGS AF: 0.999 AC: 3473 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Pathogenic:3 Benign:8 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Sep 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant represents a RefSeq error. The hg19 reference base (c.1720A) is the minor allele. This allele (A) has been identified in 4.71% (1098/23336) of Afri can chromosomes in gnomAD (http://gnomad.broadinstitute.org) and thus meets crit eria to be classified as benign.

Maturity-onset diabetes of the young type 3 Benign:1 Other:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

Reduced delayed hypersensitivity Pathogenic:1

Phenosystems SA

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Symphalangism affecting the proximal phalanx of the 4th finger Pathogenic:1

Phenosystems SA

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breast carcinoma Pathogenic:1

Phenosystems SA

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Benign:1

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Monogenic diabetes Benign:1

Apr 18, 2022

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.1720A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to glycine at codon 574 (p.(Ser574Gly)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.996; however, given that the G (Gly) alternate allele has frequencies greater than or equal to95% in all subpopulations, we have recalculated the Popmax Filtering allele frequency based on the highest prevalence of the A (Ser) reference allele being found in the African/African-American subpopulation (1144/24164 = 0.0473). The newly calculated Popmax Filtering allele frequency is 0.0447, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1720A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1, BP5.

Maturity onset diabetes mellitus in young Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs1169305 with MODY3.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	7.1
DANN	Benign	0.72
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	7.1e-7	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.74
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.16
Sift	Benign	0.78	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.080
MPC		0.11
ClinPred		0.00068	T
GERP RS		2.6
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1169305; hg19: chr12-121437382; COSMIC: COSV56568164; COSMIC: COSV56568164;