12-120997784-G-T

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.1501+119G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,098,004 control chromosomes in the GnomAD database, including 71,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8634 hom., cov: 32)
  • Exomes 𝑓: 0.35 (63048 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.113

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=-0.86).
• BP6: Variant 12-120997784-G-T is Benign according to our data. Variant chr12-120997784-G-T is described in ClinVar as [Benign]. Clinvar id is 676877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120997784-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1501+119G>T		intron_variant		ENST00000257555.11
HNF1A	NM_001306179.2	c.1501+119G>T		intron_variant
HNF1A	NM_001406915.1	c.1309+1042G>T		intron_variant
HNF1A	XM_024449168.2	c.1501+119G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1501+119G>T		intron_variant		1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48271 AN: 151952 Hom.: 8631 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.401 AC: 60157 AN: 150168 Hom.: 12655 AF XY: 0.412 AC XY: 33118 AN XY: 80318

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.487

Gnomad SAS exome AF: 0.519

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.355 AC: 335349 AN: 945932 Hom.: 63048 Cov.: 13 AF XY: 0.364 AC XY: 175919 AN XY: 483838

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.503

Gnomad4 EAS exome AF: 0.522

Gnomad4 SAS exome AF: 0.511

Gnomad4 FIN exome AF: 0.369

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.317 AC: 48273 AN: 152072 Hom.: 8634 Cov.: 32 AF XY: 0.327 AC XY: 24317 AN XY: 74360

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.488

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.372

Alfa AF: 0.358 Hom.: 22220

Bravo AF: 0.308

Asia WGS AF: 0.477 AC: 1654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
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	-0.86
Cadd	Benign	1.8
Dann	Benign	0.57

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: rs2259816; hg19: chr12-121435587; COSMIC: COSV57463646; COSMIC: COSV57463646;