12-120994499-T-G

Variant names:

• chr12-120994499-T-G
• rs1169302
• NM_000545.8:c.955+94T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 37 publications found

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]

HNF1A Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.955+94T>G		intron_variant	Intron 4 of 9	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.955+94T>G		intron_variant	Intron 4 of 9		NP_001293108.2
HNF1A	NM_001406915.1	c.955+94T>G		intron_variant	Intron 4 of 8		NP_001393844.1
HNF1A	XM_024449168.2	c.955+94T>G		intron_variant	Intron 4 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.955+94T>G		intron_variant	Intron 4 of 9	1	NM_000545.8	ENSP00000257555.5

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

African (AFR) AF: 0.272 AC: 7764 AN: 28574

American (AMR) AF: 0.436 AC: 12810 AN: 29350

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 10608 AN: 20650

East Asian (EAS) AF: 0.700 AC: 24490 AN: 34986

South Asian (SAS) AF: 0.517 AC: 35059 AN: 67850

European-Finnish (FIN) AF: 0.467 AC: 21308 AN: 45618

Middle Eastern (MID) AF: 0.524 AC: 2687 AN: 5124

European-Non Finnish (NFE) AF: 0.433 AC: 419447 AN: 967922

Other (OTH) AF: 0.455 AC: 23923 AN: 52536

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

African (AFR) AF: 0.282 AC: 11677 AN: 41472

American (AMR) AF: 0.431 AC: 6590 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3468

East Asian (EAS) AF: 0.719 AC: 3721 AN: 5172

South Asian (SAS) AF: 0.523 AC: 2526 AN: 4826

European-Finnish (FIN) AF: 0.475 AC: 5027 AN: 10576

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29428 AN: 67948

Other (OTH) AF: 0.435 AC: 918 AN: 2110

Alfa AF: 0.418 Hom.: 24313

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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