12-121001112-G-A

Position:

chr12-121001112-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000545.8(HNF1A):c.1816G>A(p.Gly606Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

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

Exomes 𝑓: 0.000029 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:1

Conservation

PhyloP100: 2.55

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07462931).

BP6

Variant 12-121001112-G-A is Benign according to our data. Variant chr12-121001112-G-A is described in ClinVar as [Benign]. Clinvar id is 1687069.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-121001112-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.1816G>A	p.Gly606Ser	missense_variant	10/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
C12orf43	NM_022895.3 link	c.*3041C>T		3_prime_UTR_variant	6/6	ENST00000288757.7	NP_075046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.1816G>A	p.Gly606Ser	missense_variant	10/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7
C12orf43	ENST00000288757 link	c.*3041C>T		3_prime_UTR_variant	6/6	1	NM_022895.3	ENSP00000288757.5		Q96C57

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152216

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250720

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000496

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department Of Endocrinology, Sanjay Gandhi Postgraduate Institute Of Medical Sciences

Aug 15, 2023

Heterozygous missense variation in exon 9 of the HNF1A gene (chr12:g.121001112G>A) that results in the amino acid substitution of Serine for Glycine at codon 637. The variant has not been reported in the 1000 genomes database and has a frequency of 0.000007 in the gnomAD genomes database. The in silico prediction of the variant is damaging by MutationTaster2, and benign by PolyPhen2 and SIFT. The variant has previously been described in a patient with suspected MODY (PMID: 22432108). However, a later publication examining the functional significance of the variant found that it was of uncertain significance/likely benign (PMID: 32910913). PP2, BP6 -

Monogenic diabetes

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 17, 2022

The c.1816G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to serine at codon 606 (p.(Gly606Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001763, which is greater than or equal to the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). Functional studies demonstrated the p.Gly606Ser protein has DNA binding above 75% of wild type and abnormal nuclear localization/transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to insufficient clinical information, and PP4 cannot be applied (PMID: 22432108). In summary, c.1816G>A 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, BS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Uncertain

0.45

.;T;.;T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.075

T;T;T;T;T

MetaSVM

Benign

-0.70

PrimateAI

Benign

0.38

PROVEAN

Benign

0.20

N;.;.;N;N

REVEL

Uncertain

0.48

Sift

Benign

0.88

T;.;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0030

.;.;.;.;B

Vest4

0.20

MutPred

0.36

.;.;.;.;Gain of phosphorylation at G613 (P = 0.0248);

MVP

0.98

MPC

0.12

ClinPred

0.017

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.55

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