14-77214730-A-C

Variant names:

• chr14-77214730-A-C
• rs8014408
• NM_020431.4:c.-14+1222A>C

Variant summary

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

The NM_020431.4(TMEM63C):​c.-14+1222A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 151,108 control chromosomes in the GnomAD database, including 6,258 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 0.26 (6258 hom., cov: 28)
• Consequence: TMEM63C NM_020431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.874
• Publications: 2 publications found

Genes affected

TMEM63C (HGNC:23787): (transmembrane protein 63C) Enables calcium activated cation channel activity. Involved in cation transport. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. Biomarker of focal segmental glomerulosclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TMEM63C Gene-Disease associations (from GenCC):

• spastic paraplegia 87, autosomal recessive

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics

ENSG00000259164 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM63C	NM_020431.4	c.-14+1222A>C		intron_variant	Intron 2 of 23	ENST00000298351.5	NP_065164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM63C	ENST00000298351.5	c.-14+1222A>C		intron_variant	Intron 2 of 23	1	NM_020431.4	ENSP00000298351.4
ENSG00000259164	ENST00000557752.1	n.137-4071A>C		intron_variant	Intron 2 of 5	5		ENSP00000456507.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38742 AN: 150986 Hom.: 6253 Cov.: 28

Gnomad AFR AF: 0.0833

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.262

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.256 AC: 38745 AN: 151108 Hom.: 6258 Cov.: 28 AF XY: 0.260 AC XY: 19152 AN XY: 73750

African (AFR) AF: 0.0832 AC: 3422 AN: 41120

American (AMR) AF: 0.228 AC: 3459 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 960 AN: 3466

East Asian (EAS) AF: 0.613 AC: 3121 AN: 5090

South Asian (SAS) AF: 0.495 AC: 2362 AN: 4774

European-Finnish (FIN) AF: 0.277 AC: 2886 AN: 10420

Middle Eastern (MID) AF: 0.310 AC: 90 AN: 290

European-Non Finnish (NFE) AF: 0.319 AC: 21598 AN: 67748

Other (OTH) AF: 0.261 AC: 547 AN: 2094

Alfa AF: 0.273 Hom.: 2963

Bravo AF: 0.244

Asia WGS AF: 0.501 AC: 1742 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.3
DANN	Benign	0.81
PhyloP100		-0.87
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: rs8014408; hg19: chr14-77681073;