rs1169310

Variant names:

• chr12-121001630-G-A
• rs1169310
• ENST00000540108.1:n.*1774G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-121001630-G-A
• chr12-121001630-G-C

Variant summary

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

The ENST00000540108.1(HNF1A):​n.*1774G>A 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 0.37 in 441,510 control chromosomes in the GnomAD database, including 32,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8635 hom., cov: 31)
  • Exomes 𝑓: 0.40 (24288 hom.)
• Consequence: HNF1A ENST00000540108.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.148
• Publications: 59 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]

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-121001630-G-A is Benign according to our data. Variant chr12-121001630-G-A is described in ClinVar as Benign. ClinVar VariationId is 307468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.*438G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000257555.11	NP_000536.6
C12orf43	NM_022895.3	c.*2523C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000288757.7	NP_075046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.*438G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_000545.8	ENSP00000257555.5
C12orf43	ENST00000288757.7	c.*2523C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_022895.3	ENSP00000288757.5

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48258 AN: 151810 Hom.: 8632 Cov.: 31

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.367

GnomAD4 exome AF: 0.398 AC: 115123 AN: 289584 Hom.: 24288 Cov.: 0 AF XY: 0.411 AC XY: 62495 AN XY: 151962

African (AFR) AF: 0.145 AC: 1360 AN: 9376

American (AMR) AF: 0.397 AC: 5783 AN: 14556

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 4980 AN: 9768

East Asian (EAS) AF: 0.525 AC: 10320 AN: 19662

South Asian (SAS) AF: 0.517 AC: 23042 AN: 44580

European-Finnish (FIN) AF: 0.360 AC: 3241 AN: 9012

Middle Eastern (MID) AF: 0.568 AC: 1599 AN: 2814

European-Non Finnish (NFE) AF: 0.359 AC: 58434 AN: 162976

Other (OTH) AF: 0.378 AC: 6364 AN: 16840

GnomAD4 genome AF: 0.318 AC: 48259 AN: 151926 Hom.: 8635 Cov.: 31 AF XY: 0.327 AC XY: 24249 AN XY: 74228

African (AFR) AF: 0.146 AC: 6038 AN: 41478

American (AMR) AF: 0.392 AC: 5989 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1751 AN: 3456

East Asian (EAS) AF: 0.490 AC: 2511 AN: 5128

South Asian (SAS) AF: 0.512 AC: 2472 AN: 4824

European-Finnish (FIN) AF: 0.384 AC: 4056 AN: 10554

Middle Eastern (MID) AF: 0.569 AC: 165 AN: 290

European-Non Finnish (NFE) AF: 0.356 AC: 24146 AN: 67906

Other (OTH) AF: 0.373 AC: 786 AN: 2110

Alfa AF: 0.342 Hom.: 24298

Bravo AF: 0.309

Asia WGS AF: 0.479 AC: 1663 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Type 2 diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in this 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Maturity-onset diabetes of the young type 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.98
DANN	Benign	0.51
PhyloP100		-0.15
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: rs1169310; hg19: chr12-121439433; COSMIC: COSV99982345; COSMIC: COSV99982345;