rs1169294

chr12-120988791-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000545.8(HNF1A):c.327-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,595,190 control chromosomes in the GnomAD database, including 86,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7146 hom., cov: 33)
  • Exomes 𝑓: 0.33 (78905 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.273

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-120988791-G-A is Benign according to our data. Variant chr12-120988791-G-A is described in ClinVar as [Benign]. Clinvar id is 673535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120988791-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.327-42G>A		intron_variant		ENST00000257555.11
HNF1A	NM_001306179.2	c.327-42G>A		intron_variant
HNF1A	NM_001406915.1	c.327-42G>A		intron_variant
HNF1A	XM_024449168.2	c.327-42G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.327-42G>A		intron_variant		1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44742 AN: 152044 Hom.: 7145 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.313

GnomAD3 exomes AF: 0.348 AC: 84443 AN: 242538 Hom.: 15053 AF XY: 0.353 AC XY: 46269 AN XY: 131146

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.406

Gnomad SAS exome AF: 0.411

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.327 AC: 471715 AN: 1443028 Hom.: 78905 Cov.: 30 AF XY: 0.330 AC XY: 237293 AN XY: 718632

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.452

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.294 AC: 44744 AN: 152162 Hom.: 7146 Cov.: 33 AF XY: 0.302 AC XY: 22486 AN XY: 74382

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.448

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.399

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.319

Alfa AF: 0.318 Hom.: 2148

Bravo AF: 0.284

Asia WGS AF: 0.399 AC: 1385 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:1

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 rs1169294 with MODY3. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.25
Dann	Benign	0.56

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: rs1169294; hg19: chr12-121426594; COSMIC: COSV57460094;