12-121000579-T-C

Variant names:

• chr12-121000579-T-C
• rs1169307
• NM_022895.3:c.*3574A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022895.3(C12orf43):​c.*3574A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 219,442 control chromosomes in the GnomAD database, including 41,542 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.59 (27791 hom., cov: 32)
  • Exomes 𝑓: 0.62 (13751 hom.)
• Consequence: C12orf43 NM_022895.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 31 publications found

Genes affected

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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf43	NM_022895.3	c.*3574A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000288757.7	NP_075046.1
HNF1A	NM_000545.8	c.1769-486T>C		intron_variant	Intron 9 of 9	ENST00000257555.11	NP_000536.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf43	ENST00000288757.7	c.*3574A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_022895.3	ENSP00000288757.5
HNF1A	ENST00000257555.11	c.1769-486T>C		intron_variant	Intron 9 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89722 AN: 151896 Hom.: 27759 Cov.: 32

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.805

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.732

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.637

GnomAD4 exome AF: 0.624 AC: 42049 AN: 67428 Hom.: 13751 Cov.: 0 AF XY: 0.638 AC XY: 22336 AN XY: 34998

African (AFR) AF: 0.343 AC: 655 AN: 1908

American (AMR) AF: 0.776 AC: 2925 AN: 3770

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 889 AN: 1430

East Asian (EAS) AF: 0.869 AC: 2647 AN: 3046

South Asian (SAS) AF: 0.751 AC: 7291 AN: 9708

European-Finnish (FIN) AF: 0.542 AC: 1613 AN: 2978

Middle Eastern (MID) AF: 0.614 AC: 156 AN: 254

European-Non Finnish (NFE) AF: 0.582 AC: 23751 AN: 40778

Other (OTH) AF: 0.597 AC: 2122 AN: 3556

GnomAD4 genome AF: 0.591 AC: 89797 AN: 152014 Hom.: 27791 Cov.: 32 AF XY: 0.599 AC XY: 44477 AN XY: 74294

African (AFR) AF: 0.421 AC: 17449 AN: 41440

American (AMR) AF: 0.751 AC: 11482 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2305 AN: 3470

East Asian (EAS) AF: 0.868 AC: 4475 AN: 5158

South Asian (SAS) AF: 0.804 AC: 3868 AN: 4810

European-Finnish (FIN) AF: 0.588 AC: 6199 AN: 10546

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.616 AC: 41860 AN: 67980

Other (OTH) AF: 0.640 AC: 1355 AN: 2116

Alfa AF: 0.619 Hom.: 49338

Bravo AF: 0.595

Asia WGS AF: 0.832 AC: 2892 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.35
DANN	Benign	0.19
PhyloP100		-1.4
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: rs1169307; hg19: chr12-121438382;