10-71761773-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022153.2(VSIR):c.336C>A(p.Asp112Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VSIR NM_022153.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0820

Genes affected

VSIR (HGNC:30085): (V-set immunoregulatory receptor) Enables endopeptidase activator activity; enzyme binding activity; and identical protein binding activity. Involved in several processes, including negative regulation of cytokine production; positive regulation of macromolecule metabolic process; and regulation of T cell activation. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.111328065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSIR	NM_022153.2	c.336C>A	p.Asp112Glu	missense_variant	2/7	ENST00000394957.8
CDH23	NM_022124.6	c.4846-15907G>T		intron_variant		ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSIR	ENST00000394957.8	c.336C>A	p.Asp112Glu	missense_variant	2/7	1	NM_022153.2	P1
CDH23	ENST00000224721.12	c.4846-15907G>T		intron_variant		5	NM_022124.6	P1
VSIR	ENST00000481568.2	n.172C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.336C>A (p.D112E) alteration is located in exon 2 (coding exon 2) of the C10orf54 gene. This alteration results from a C to A substitution at nucleotide position 336, causing the aspartic acid (D) at amino acid position 112 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	10
Dann	Uncertain	0.98
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.51	D;N
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Uncertain	0.027	D
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.053
MutPred		0.60		Gain of helix (P = 0.132);
MVP		0.067
MPC		0.29
ClinPred		0.057	T
GERP RS		-1.9
Varity_R		0.21
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-73521530;