12-121001630-G-A

Position:

• chr12-121001630-G-A

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.*438G>A variant causes a 3 prime UTR 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 NM_000545.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.148

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.*438G>A		3_prime_UTR_variant	10/10	ENST00000257555.11	NP_000536.6
C12orf43	NM_022895.3	c.*2523C>T		3_prime_UTR_variant	6/6	ENST00000288757.7	NP_075046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.*438G>A		3_prime_UTR_variant	10/10	1	NM_000545.8	ENSP00000257555	P4
C12orf43	ENST00000288757.7	c.*2523C>T		3_prime_UTR_variant	6/6	1	NM_022895.3	ENSP00000288757	P2

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

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.510

Gnomad4 EAS exome AF: 0.525

Gnomad4 SAS exome AF: 0.517

Gnomad4 FIN exome AF: 0.360

Gnomad4 NFE exome AF: 0.359

Gnomad4 OTH exome AF: 0.378

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

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.373

Alfa AF: 0.346 Hom.: 5693

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

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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: rs1169310; hg19: chr12-121439433;