12-121001076-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM5BP4_ModerateBP6_Very_StrongBS2

The NM_000545.8(HNF1A):c.1780A>G(p.Ser594Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S594I) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:1

Conservation

PhyloP100: 5.82

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:

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

C12orf43 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-121001077-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1315998.Status of the report is reviewed_by_expert_panel, 3 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.22481379).

BP6

Variant 12-121001076-A-G is Benign according to our data. Variant chr12-121001076-A-G is described in ClinVar as [Benign]. Clinvar id is 1700002.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAdExome at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8 linkuse as main transcript	c.1780A>G	p.Ser594Gly	missense_variant	10/10	ENST00000257555.11
C12orf43	NM_022895.3 linkuse as main transcript	c.*3077T>C		3_prime_UTR_variant	6/6	ENST00000288757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1780A>G	p.Ser594Gly	missense_variant	10/10	1	NM_000545.8	P4
C12orf43	ENST00000288757.7 linkuse as main transcript	c.*3077T>C		3_prime_UTR_variant	6/6	1	NM_022895.3	P2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000560

AC:

AN:

250012

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461280

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jul 01, 2022

The c.1780A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to glycine at codon 594 (p.(Ser594Gly)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD v2.1.1 of 0.0002499, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). Another missense variant, c.1781G>T, p.Ser594Ile, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ser594Gly (PM5_Supporting). In summary, c.1780A>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 9/30/21): BA1, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.0041

BayesDel_noAF

Uncertain

0.090

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Uncertain

0.76

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

N;.;.;N;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0060

D;.;.;D;D

Sift4G

Uncertain

0.011

D;T;D;D;T

Polyphen

0.99

.;.;.;.;D

Vest4

0.42

MutPred

0.46

.;.;.;.;Loss of phosphorylation at S601 (P = 0.017);

MVP

0.89

MPC

0.19

ClinPred

0.37

GERP RS

6.1

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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