12-120999579-A-G

Position:

chr12-120999579-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP5BA1

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

Scores

Clinical Significance

Benign reviewed by expert panel P:3B:8O:2

Conservation

PhyloP100: 0.738

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8 linkuse as main transcript	c.1720A>G	p.Ser574Gly	missense_variant	9/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 linkuse as main transcript	c.1741A>G	p.Ser581Gly	missense_variant	9/10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 linkuse as main transcript	c.1528A>G	p.Ser510Gly	missense_variant	8/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.1813A>G	p.Ser605Gly	missense_variant	8/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1720A>G	p.Ser574Gly	missense_variant	9/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.987

AC:

150280

AN:

152240

Hom.:

74204

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.996

AC:

242441

AN:

243302

Hom.:

120811

AF XY:

0.997

AC XY:

132201

AN XY:

132560

show subpopulations

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 SAS 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.:

AF XY:

0.999

AC XY:

725656

AN XY:

726522

show subpopulations

Gnomad4 AFR exome

AF:

0.953

Gnomad4 AMR exome

AF:

0.997

Gnomad4 ASJ exome

AF:

1.00

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.997

GnomAD4 genome

AF:

0.987

AC:

150397

AN:

152358

Hom.:

74262

Cov.:

AF XY:

0.988

AC XY:

73612

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.955

Gnomad4 AMR

AF:

0.995

Gnomad4 ASJ

AF:

1.00

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

1.00

Gnomad4 OTH

AF:

0.991

Alfa

AF:

0.993

Hom.:

36535

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:3Benign:8Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 10, 2018	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Maturity-onset diabetes of the young type 3

Benign:1Other:1

not provided, no classification provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Reduced delayed hypersensitivity

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Phenosystems SA

- -

Symphalangism affecting the proximal phalanx of the 4th finger

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Phenosystems SA

- -

Breast carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Phenosystems SA

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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. -

Monogenic diabetes

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 18, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Benign

7.1

DANN

Benign

0.72

DEOGEN2

Uncertain

0.42

.;T;.;T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.040

T;T;T;T;T

MetaRNN

Benign

7.1e-7

T;T;T;T;T

MetaSVM

Benign

-0.95

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.080

N;.;.;N;N

REVEL

Benign

0.16

Sift

Benign

0.78

T;.;.;T;T

Sift4G

Benign

0.51

T;T;T;T;T

Polyphen

0.0

.;.;.;.;B

Vest4

0.080

MPC

0.11

ClinPred

0.00068

GERP RS

2.6

gMVP

0.37

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over