rs2464195

Positions:

• chr12-120997672-G-A
• chr12-120997672-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000545.8(HNF1A):​c.1501+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,601,934 control chromosomes in the GnomAD database, including 110,205 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.32 (8637 hom., cov: 33)
  • Exomes 𝑓: 0.37 (101568 hom.)
• Consequence: HNF1A NM_000545.8 splice_region, intron
• Scores: Splicing: ADA: 0.00001420
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• Conservation: PhyloP100: -2.15

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2227126E-5).
• BP6: Variant 12-120997672-G-A is Benign according to our data. Variant chr12-120997672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129231.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=1, not_provided=1}. Variant chr12-120997672-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1501+7G>A		splice_region_variant, intron_variant		ENST00000257555.11
HNF1A	NM_001306179.2	c.1501+7G>A		splice_region_variant, intron_variant
HNF1A	NM_001406915.1	c.1309+930G>A		intron_variant
HNF1A	XM_024449168.2	c.1501+7G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1501+7G>A		splice_region_variant, intron_variant		1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48276 AN: 152006 Hom.: 8635 Cov.: 33

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.365

GnomAD3 exomes AF: 0.390 AC: 90608 AN: 232434 Hom.: 18320 AF XY: 0.401 AC XY: 50497 AN XY: 126044

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.501

Gnomad EAS exome AF: 0.485

Gnomad SAS exome AF: 0.521

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.364

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.368 AC: 533834 AN: 1449810 Hom.: 101568 Cov.: 34 AF XY: 0.374 AC XY: 269555 AN XY: 720574

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.524

Gnomad4 SAS exome AF: 0.517

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.352

Gnomad4 OTH exome AF: 0.378

GnomAD4 genome AF: 0.317 AC: 48277 AN: 152124 Hom.: 8637 Cov.: 33 AF XY: 0.326 AC XY: 24281 AN XY: 74370

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.513

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.371

Alfa AF: 0.342 Hom.: 4111

Bravo AF: 0.309

TwinsUK AF: 0.353 AC: 1308

ALSPAC AF: 0.356 AC: 1372

ESP6500AA AF: 0.141 AC: 622

ESP6500EA AF: 0.366 AC: 3150

ExAC AF: 0.373 AC: 45188

Asia WGS AF: 0.477 AC: 1654 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, 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 multiple cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, no sufficient evidence is found to support association of rs2464195 with T2DM or MODY. -

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nonpapillary renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.055
DANN	Benign	0.57
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.000022	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
Sift4G	Benign	0.23	T
Vest4		0.047
ClinPred		0.019	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
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: rs2464195; hg19: chr12-121435475; COSMIC: COSV99982163; COSMIC: COSV99982163;