rs1555212006

chr12-120994244-A-Cchr12-120994244-A-Gchr12-120994244-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000545.8(HNF1A):c.794A>C(p.Tyr265Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging 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. Y265C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 8.86

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120994244-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 1338571.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.794A>C	p.Tyr265Ser	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.794A>C	p.Tyr265Ser	missense_variant	4/10
HNF1A	NM_001406915.1	c.794A>C	p.Tyr265Ser	missense_variant	4/9
HNF1A	XM_024449168.2	c.794A>C	p.Tyr265Ser	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.794A>C	p.Tyr265Ser	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2023	Variant summary: HNF1A c.794A>C (p.Tyr265Ser) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.794A>C in individuals affected with Maturity Onset Diabetes Of The Young 3 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs1555212006 with MODY3. -

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 15, 2022

The c.794A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to serine at codon 265 (p.Tyr265Ser) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.938, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.794A>G (p.Tyr265Cys), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.794A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3 -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 09, 2022

Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.7	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.034	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.90
MutPred		0.69		Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.99

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: rs1555212006; hg19: chr12-121432047;