12-120994499-T-G

Position:

• chr12-120994499-T-G

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.955+94T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,404,666 control chromosomes in the GnomAD database, including 140,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13512 hom., cov: 32)
  • Exomes 𝑓: 0.45 (126557 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.568

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=-0.87).
• BP6: Variant 12-120994499-T-G is Benign according to our data. Variant chr12-120994499-T-G is described in ClinVar as [Benign]. Clinvar id is 676860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.955+94T>G		intron_variant		ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.955+94T>G		intron_variant			NP_001293108.2
HNF1A	NM_001406915.1	c.955+94T>G		intron_variant			NP_001393844.1
HNF1A	XM_024449168.2	c.955+94T>G		intron_variant			XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.955+94T>G		intron_variant		1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62226 AN: 151940 Hom.: 13502 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.431

GnomAD4 exome AF: 0.446 AC: 558096 AN: 1252610 Hom.: 126557 AF XY: 0.448 AC XY: 275270 AN XY: 614938

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.436

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.517

Gnomad4 FIN exome AF: 0.467

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.455

GnomAD4 genome AF: 0.409 AC: 62258 AN: 152056 Hom.: 13512 Cov.: 32 AF XY: 0.417 AC XY: 30974 AN XY: 74330

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.431

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.719

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.435

Alfa AF: 0.420 Hom.: 18123

Bravo AF: 0.399

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.87
CADD	Benign	0.59
DANN	Benign	0.37

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: rs1169302; hg19: chr12-121432302; COSMIC: COSV57467159; COSMIC: COSV57467159;