12-120994166-C-T

Position:

• chr12-120994166-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM5 PP3 BS2

The ENST00000257555.11(HNF1A):​c.716C>T​(p.Ala239Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,612,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A239T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: HNF1A ENST00000257555.11 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:2 O:1
• Conservation: PhyloP100: 7.50

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000257555.11
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120994165-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3370452.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.716C>T	p.Ala239Val	missense_variant, splice_region_variant	4/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.716C>T	p.Ala239Val	missense_variant, splice_region_variant	4/10		NP_001293108.2
HNF1A	NM_001406915.1	c.716C>T	p.Ala239Val	missense_variant, splice_region_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2	c.716C>T	p.Ala239Val	missense_variant, splice_region_variant	4/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.716C>T	p.Ala239Val	missense_variant, splice_region_variant	4/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000186 AC: 46 AN: 246990 Hom.: 0 AF XY: 0.000180 AC XY: 24 AN XY: 133678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000664

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1460504 Hom.: 0 Cov.: 33 AF XY: 0.0000647 AC XY: 47 AN XY: 726400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000968

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000215

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 12488961, 24728327, 28395978, 26556299, 32041611) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	- -

not specified Uncertain:1 Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 27, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified in HGMD as DM and has been reported in 1 patient with diabetes and one healthy patient. This variant is present in ClinVar with no interpretation (Submission by ITMI). The Max MAF in ExAC is 0.035%. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2024	Variant summary: HNF1A c.716C>T (p.Ala239Val) results in a non-conservative amino acid change located in the Homeodomain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 246990 control chromosomes. The observed variant frequency is approximately 7 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). c.716C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (Karaca_2017). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Tonooka_2002). The following publications have been ascertained in the context of this evaluation (PMID: 17924661, 36703223, 28395978, 12488961). ClinVar contains an entry for this variant (Variation ID: 134510). Based on the evidence outlined above, the variant was classified as likely benign. -

Maturity-onset diabetes of the young type 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 18, 2024	- -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely risk allele, flagged submission

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 rs587778397 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	.;D;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	D;.;D;D
REVEL	Pathogenic	0.86
Sift	Benign	0.036	D;.;D;D
Sift4G	Uncertain	0.048	D;T;T;D
Polyphen		1.0	.;.;.;D
Vest4		0.91
MVP		0.98
MPC		2.2
ClinPred		0.25	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587778397; hg19: chr12-121431969;