12-121000508-C-T

Variant names:

• chr12-121000508-C-T
• rs1169306
• NM_022895.3:c.*3645G>A

Variant summary

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

The NM_022895.3(C12orf43):​c.*3645G>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 0.323 in 179,720 control chromosomes in the GnomAD database, including 10,655 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 0.32 (8732 hom., cov: 32)
  • Exomes 𝑓: 0.34 (1923 hom.)
• Consequence: C12orf43 NM_022895.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 19 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf43	NM_022895.3	c.*3645G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000288757.7	NP_075046.1
HNF1A	NM_000545.8	c.1769-557C>T		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.*3645G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_022895.3	ENSP00000288757.5
HNF1A	ENST00000257555.11	c.1769-557C>T		intron_variant	Intron 9 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48533 AN: 151934 Hom.: 8728 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.370

GnomAD4 exome AF: 0.343 AC: 9484 AN: 27668 Hom.: 1923 Cov.: 0 AF XY: 0.354 AC XY: 4979 AN XY: 14072

African (AFR) AF: 0.0912 AC: 52 AN: 570

American (AMR) AF: 0.382 AC: 1174 AN: 3070

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 179 AN: 406

East Asian (EAS) AF: 0.468 AC: 664 AN: 1418

South Asian (SAS) AF: 0.484 AC: 1542 AN: 3188

European-Finnish (FIN) AF: 0.283 AC: 253 AN: 894

Middle Eastern (MID) AF: 0.554 AC: 41 AN: 74

European-Non Finnish (NFE) AF: 0.309 AC: 5127 AN: 16614

Other (OTH) AF: 0.315 AC: 452 AN: 1434

GnomAD4 genome AF: 0.319 AC: 48536 AN: 152052 Hom.: 8732 Cov.: 32 AF XY: 0.328 AC XY: 24398 AN XY: 74328

African (AFR) AF: 0.146 AC: 6059 AN: 41498

American (AMR) AF: 0.393 AC: 5993 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1760 AN: 3472

East Asian (EAS) AF: 0.490 AC: 2522 AN: 5152

South Asian (SAS) AF: 0.518 AC: 2498 AN: 4820

European-Finnish (FIN) AF: 0.385 AC: 4064 AN: 10558

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24339 AN: 67972

Other (OTH) AF: 0.375 AC: 792 AN: 2112

Alfa AF: 0.195 Hom.: 838

Bravo AF: 0.310

Asia WGS AF: 0.480 AC: 1664 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.011
DANN	Benign	0.29
PhyloP100		-1.1
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: rs1169306; hg19: chr12-121438311;