rs555681479

Positions:

• chr12-120994351-G-A
• chr12-120994351-G-C
• chr12-120994351-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000545.8(HNF1A):​c.901G>A​(p.Ala301Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,600,064 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23773482).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.901G>A	p.Ala301Thr	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.901G>A	p.Ala301Thr	missense_variant	4/10
HNF1A	NM_001406915.1	c.901G>A	p.Ala301Thr	missense_variant	4/9
HNF1A	XM_024449168.2	c.901G>A	p.Ala301Thr	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.901G>A	p.Ala301Thr	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000451 AC: 10 AN: 221838 Hom.: 0 AF XY: 0.0000417 AC XY: 5 AN XY: 119982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000322

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.0000596

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000530

Gnomad NFE exome AF: 0.0000506

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.0000173 AC: 25 AN: 1447908 Hom.: 0 Cov.: 35 AF XY: 0.0000195 AC XY: 14 AN XY: 719076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000713

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000488 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 301 of the HNF1A protein (p.Ala301Thr). This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 10027593, 19336507). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function. ClinVar contains an entry for this variant (Variation ID: 586796). -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2017	- -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Madras Diabetes Research Foundation

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	17
DANN	Benign	0.92
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Uncertain	-0.0046	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.23	N;.;N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.50	T;.;T;T
Sift4G	Benign	0.77	T;T;T;T
Polyphen		0.037	.;.;.;B
Vest4		0.25
MutPred		0.53		Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);
MVP		0.96
MPC		0.12
ClinPred		0.034	T
GERP RS		3.8
gMVP		0.72

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: rs555681479; hg19: chr12-121432154;