12-120978797-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PM1 PM5 PP5_Strong BP4 BS2

The NM_000545.8(HNF1A):c.29C>T(p.Thr10Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T10P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4
• Conservation: PhyloP100: 2.46

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 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000545.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120978796-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1675061.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant 12-120978797-C-T is Pathogenic according to our data. Variant chr12-120978797-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 435422.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2}. Variant chr12-120978797-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.40481442).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.29C>T	p.Thr10Met	missense_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.29C>T	p.Thr10Met	missense_variant	1/10
HNF1A	NM_001406915.1	c.29C>T	p.Thr10Met	missense_variant	1/9
HNF1A	XM_024449168.2	c.29C>T	p.Thr10Met	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.29C>T	p.Thr10Met	missense_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1847G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247688 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134830

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460818 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726736

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 3 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 13, 2015	- -

Monogenic diabetes Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Mar 28, 2022	The c.29C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 10 (p.(Thr10Met)) of NM_000545.8. This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). While the variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate could not be applied because c.29C>T does not meet the criteria to apply PM2_Supporting (>=0.00002 allele frequency in the European Non-Finnish population and >=1 copy in any other subpopulation)(PMIDs 30155490, 18003757, internal lab contributors). Another missense variant, c.28A>C (p.Thr10Pro) has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant 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 9/30/21): PM1_Supporting, PP4, PM5_Suppporting. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Thr10Met variant in HNF1A has been reported in at least 3 individuals with Monogenic Diabetes (PMID: 16917892, 18003757, 28938416), and has been identified in 0.01290% (2/15504) of African chromosomes, 0.005794% (2/34520) of Latino chromosomes, and 0.005473% (1/18270) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs774637975). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr10Met variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting (Richards 2015). -

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. Sufficient evidence is found to confer the association of this particular variant rs774637975 with MODY3. -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Benign	23
Dann	Benign	0.90
Eigen	Benign	-0.049
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.40	T;T;T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.79	N;.;.;.;N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.023	D;.;.;.;D;D
Sift4G	Uncertain	0.047	D;D;T;D;T;D
Polyphen		0.96	.;.;.;.;.;D
Vest4		0.25
MVP		0.97
MPC		0.17
ClinPred		0.56	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.58

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: rs774637975; hg19: chr12-121416600; COSMIC: COSV99982822;