12-120997784-G-T

Variant names:

• chr12-120997784-G-T
• rs2259816
• ENST00000535955.5:n.336G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000535955.5(HNF1A):​n.336G>T variant causes a non coding transcript exon 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 ENST00000535955.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.113
• Publications: 126 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=-0.86).
• BP6: Variant 12-120997784-G-T is Benign according to our data. Variant chr12-120997784-G-T is described in ClinVar as Benign. ClinVar VariationId is 676877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000535955.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.1501+119G>T		intron	N/A	NP_000536.6
	HNF1A	NM_001306179.2		c.1501+119G>T		intron	N/A	NP_001293108.2
	HNF1A	NM_001406915.1		c.1309+1042G>T		intron	N/A	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000535955.5	TSL:1	n.336G>T		non_coding_transcript_exon	Exon 2 of 2
	HNF1A	ENST00000538626.2	TSL:1	n.484G>T		non_coding_transcript_exon	Exon 2 of 2
	HNF1A	ENST00000538646.5	TSL:1	n.*596G>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000443964.1

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

GnomAD2 exomes AF: 0.401 AC: 60157 AN: 150168 AF XY: 0.412

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 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

African (AFR) AF: 0.132 AC: 3084 AN: 23438

American (AMR) AF: 0.404 AC: 14205 AN: 35136

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 11141 AN: 22164

East Asian (EAS) AF: 0.522 AC: 17553 AN: 33596

South Asian (SAS) AF: 0.511 AC: 35615 AN: 69684

European-Finnish (FIN) AF: 0.369 AC: 17777 AN: 48144

Middle Eastern (MID) AF: 0.546 AC: 2616 AN: 4790

European-Non Finnish (NFE) AF: 0.327 AC: 217538 AN: 665990

Other (OTH) AF: 0.368 AC: 15820 AN: 42990

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

African (AFR) AF: 0.144 AC: 5991 AN: 41534

American (AMR) AF: 0.392 AC: 5981 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1743 AN: 3468

East Asian (EAS) AF: 0.488 AC: 2517 AN: 5162

South Asian (SAS) AF: 0.512 AC: 2471 AN: 4826

European-Finnish (FIN) AF: 0.392 AC: 4138 AN: 10560

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24138 AN: 67942

Other (OTH) AF: 0.372 AC: 784 AN: 2110

Alfa AF: 0.350 Hom.: 43061

Bravo AF: 0.308

Asia WGS AF: 0.477 AC: 1654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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.

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.57
PhyloP100		-0.11
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: rs2259816; hg19: chr12-121435587; COSMIC: COSV57463646; COSMIC: COSV57463646;