11-837496-C-T

Position:

• chr11-837496-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004357.5(CD151):​c.493C>T​(p.Arg165Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CD151 NM_004357.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: -0.641

Genes affected

CD151 (HGNC:1630): (CD151 molecule (Raph blood group)) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins and other transmembrane 4 superfamily proteins. It is involved in cellular processes including cell adhesion and may regulate integrin trafficking and/or function. This protein enhances cell motility, invasion and metastasis of cancer cells. Multiple alternatively spliced transcript variants that encode the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

POLR2L (HGNC:9199): (RNA polymerase II, I and III subunit L) This gene encodes a subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains four conserved cysteines characteristic of an atypical zinc-binding domain. Like its counterpart in yeast, this subunit may be shared by the other two DNA-directed RNA polymerases. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-837496-C-T is Pathogenic according to our data. Variant chr11-837496-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1028736.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD151	NM_004357.5	c.493C>T	p.Arg165Ter	stop_gained	7/9	ENST00000397420.9	NP_004348.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD151	ENST00000397420.9	c.493C>T	p.Arg165Ter	stop_gained	7/9	1	NM_004357.5	ENSP00000380565	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249780 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135528

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460622 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 726612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epidermolysis bullosa simplex 7, with nephropathy and deafness Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 09, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Jun 09, 2020	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1028736). This variant has not been reported in the literature in individuals affected with CD151-related conditions. This variant is present in population databases (rs759213580, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg165*) in the CD151 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CD151 cause disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.39	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.87
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs759213580; hg19: chr11-837496;