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

Sel.	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	F5H0K0
	HNF1A	NM_001406915.1		c.1528A>G	p.Ser510Gly	missense	Exon 8 of 9	NP_001393844.1

Ensembl Transcripts

Sel.	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	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1741A>G	p.Ser581Gly	missense	Exon 9 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000540108.1	TSL:1	n.*1160A>G		non_coding_transcript_exon	Exon 8 of 9	ENSP00000445445.1	P20823-8

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
1	-	-	Breast carcinoma (1)
-	-	1	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 (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Maturity-onset diabetes of the young type 3 (2)
-	-	1	Monogenic diabetes (1)
-	-	1	not specified (2)
1	-	-	Reduced delayed hypersensitivity (1)
1	-	-	Symphalangism affecting the proximal phalanx of the 4th finger (1)

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;