12-120978920-G-T

Position:

• chr12-120978920-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.152G>T​(p.Gly51Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17966405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.152G>T	p.Gly51Val	missense_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.152G>T	p.Gly51Val	missense_variant	1/10
HNF1A	NM_001406915.1	c.152G>T	p.Gly51Val	missense_variant	1/9
HNF1A	XM_024449168.2	c.152G>T	p.Gly51Val	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.152G>T	p.Gly51Val	missense_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1724C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Aug 01, 2017

ACMG Criteria:PP3 (4 predictors), BP4 (5 predictors), PM2 (absent in database) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	16
DANN	Benign	0.97
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.71	T;T;T;T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationTaster	Benign	0.82	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;.;.;.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.043	D;.;.;.;D;D
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		0.0010	.;.;.;.;.;B
Vest4		0.15
MutPred		0.47		Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);
MVP		0.81
MPC		0.32
ClinPred		0.10	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.50

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

Other links and lift over

dbSNP: rs776710848; hg19: chr12-121416723;