12-120994405-G-A

Variant names:

• chr12-120994405-G-A
• rs137853240
• NM_000545.8:c.955G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_000545.8(HNF1A):​c.955G>A​(p.Gly319Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 1,587,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.90

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 -3 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.955G>A	p.Gly319Ser	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.955G>A	p.Gly319Ser	missense_variant, splice_region_variant	Exon 4 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.955G>A	p.Gly319Ser	missense_variant, splice_region_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.955G>A	p.Gly319Ser	missense_variant, splice_region_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.955G>A	p.Gly319Ser	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152194 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000627 AC: 9 AN: 1435216 Hom.: 0 Cov.: 36 AF XY: 0.00000703 AC XY: 5 AN XY: 711138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

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: 0.00000728

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HNF1A c.955G>A (p.Gly319Ser) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant, located in the exonic-splice region alters the conserved last nucleotide of exon 4 adjacent to the canonical intronic splice donor site. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Triggs-Raine_2002). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. The variant allele was found at a frequency of 0.00028 in 206130 control chromosomes, predominantly at a frequency of 0.087 among the Ontario Oji-Cree nondiabetic control chromosomes (Hegele_1999). The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.955G>A has been reported in the literature as a risk factor associated with a risk for Type 2 diabetes characterized by onset at an earlier age, higher postprandial plasma glucose, and lower body mass index (BMI) (Hegele_1999). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function (Triggs-Raine_2002). The most pronounced variant effect results in an approximately 50% reduction in transcription ability while not affecting DNA binding or protein stability in-vitro. The combination of the reduced activity of the G319S protein and abnormal splicing transcripts has been thought to increase the susceptibility to diabetes (Li_2022). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the conflicting evidence outlined above, the variant was classified as uncertain significance in association to Maturity Onset Diabetes Of The Young 3. -

Diabetes mellitus type 2, susceptibility to Other:1

Apr 02, 2002

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N;.;N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.020	D;.;D;D
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.97	.;.;.;D
Vest4		0.81
MutPred		0.46		Loss of catalytic residue at G319 (P = 0.0053);Loss of catalytic residue at G319 (P = 0.0053);Loss of catalytic residue at G319 (P = 0.0053);Loss of catalytic residue at G319 (P = 0.0053);
MVP		0.87
MPC		0.56
ClinPred		0.97	D
GERP RS		4.7
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137853240; hg19: chr12-121432208;