12-120978422-G-A

Variant names:

• chr12-120978422-G-A
• rs76729898
• ENST00000433033.4:n.153+1192C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000433033.4(HNF1A-AS1):​n.153+1192C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 419,500 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: HNF1A-AS1 ENST00000433033.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83
• Publications: 1 publications found

Genes affected

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-120978422-G-A is Benign according to our data. Variant chr12-120978422-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 389514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.-347G>A		upstream_gene_variant		ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.-347G>A		upstream_gene_variant			NP_001293108.2
HNF1A	NM_001406915.1	c.-347G>A		upstream_gene_variant			NP_001393844.1
HNF1A	XM_024449168.2	c.-347G>A		upstream_gene_variant			XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.-347G>A		upstream_gene_variant		1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 151884 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.000460 AC: 123 AN: 267498 Hom.: 0 AF XY: 0.000348 AC XY: 49 AN XY: 140808

African (AFR) AF: 0.00827 AC: 69 AN: 8346

American (AMR) AF: 0.00120 AC: 15 AN: 12474

Ashkenazi Jewish (ASJ) AF: 0.00175 AC: 15 AN: 8570

East Asian (EAS) AF: 0.00 AC: 0 AN: 17502

South Asian (SAS) AF: 0.0000245 AC: 1 AN: 40878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9426

Middle Eastern (MID) AF: 0.000919 AC: 1 AN: 1088

European-Non Finnish (NFE) AF: 0.0000390 AC: 6 AN: 153936

Other (OTH) AF: 0.00105 AC: 16 AN: 15278

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152002 Hom.: 2 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74294

African (AFR) AF: 0.00697 AC: 289 AN: 41436

American (AMR) AF: 0.00229 AC: 35 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000867 AC: 3 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67972

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00297

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Oct 05, 2016

GeneDx

Significance: Likely 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. -

Maturity onset diabetes mellitus in young Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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 rs76729898 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.63
PhyloP100		1.8
PromoterAI		-0.047	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76729898; hg19: chr12-121416225;