12-121001041-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022895.3(C12orf43):c.*3112A>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 0.365 in 1,611,356 control chromosomes in the GnomAD database, including 111,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8658 hom., cov: 32)
  • Exomes 𝑓: 0.37 (102821 hom.)
• Consequence: C12orf43 NM_022895.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0600

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-121001041-T-C is Benign according to our data. Variant chr12-121001041-T-C is described in ClinVar as [Benign]. Clinvar id is 673537.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-121001041-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C12orf43	NM_022895.3	c.*3112A>G		3_prime_UTR_variant	6/6	ENST00000288757.7
HNF1A	NM_000545.8	c.1769-24T>C		intron_variant		ENST00000257555.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C12orf43	ENST00000288757.7	c.*3112A>G		3_prime_UTR_variant	6/6	1	NM_022895.3	P2
HNF1A	ENST00000257555.11	c.1769-24T>C		intron_variant		1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48329 AN: 151914 Hom.: 8654 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.574

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.368

GnomAD3 exomes AF: 0.392 AC: 96664 AN: 246892 Hom.: 19950 AF XY: 0.403 AC XY: 53868 AN XY: 133826

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.506

Gnomad EAS exome AF: 0.492

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.369 AC: 539129 AN: 1459324 Hom.: 102821 Cov.: 41 AF XY: 0.375 AC XY: 272574 AN XY: 725964

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.364

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.318 AC: 48332 AN: 152032 Hom.: 8658 Cov.: 32 AF XY: 0.327 AC XY: 24304 AN XY: 74304

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.373

Alfa AF: 0.370 Hom.: 24114

Bravo AF: 0.309

Asia WGS AF: 0.482 AC: 1673 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	8.4
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs735396; hg19: chr12-121438844; COSMIC: COSV56566379; COSMIC: COSV56566379;