rs371365341

Positions:

• chr12-120988842-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000257555.11(HNF1A):​c.336G>A​(p.Pro112=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: HNF1A ENST00000257555.11 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.01

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-120988842-G-A is Benign according to our data. Variant chr12-120988842-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 307459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120988842-G-A is described in Lovd as [Benign]. Variant chr12-120988842-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BS2: High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.336G>A	p.Pro112=	synonymous_variant	2/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.336G>A	p.Pro112=	synonymous_variant	2/10		NP_001293108.2
HNF1A	NM_001406915.1	c.336G>A	p.Pro112=	synonymous_variant	2/9		NP_001393844.1
HNF1A	XM_024449168.2	c.336G>A	p.Pro112=	synonymous_variant	2/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.336G>A	p.Pro112=	synonymous_variant	2/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000490 AC: 123 AN: 251238 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135792

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.000304 AC XY: 221 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000262

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000354 AC: 54 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74488

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000544 Hom.: 0

Bravo AF: 0.000363

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	HNF1A: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	This variant is associated with the following publications: (PMID: 27659712, 30708140) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2020	- -

Maturity onset diabetes mellitus in young Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2016	This alteration is classified as likely 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. -
Benign, 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 rs371365341 with MODY3. -

Maturity-onset diabetes of the young type 3 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

HNF1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.59
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs371365341; hg19: chr12-121426645;