11-2377589-C-T

Variant names:

• chr11-2377589-C-T
• rs759471923
• NM_004356.4:c.40C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004356.4(CD81):​c.40C>T​(p.Leu14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,390,956 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CD81 NM_004356.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 0 publications found

Genes affected

CD81 (HGNC:1701): (CD81 molecule) 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. This protein appears to promote muscle cell fusion and support myotube maintenance. Also it may be involved in signal transduction. This gene is localized in the tumor-suppressor gene region and thus it is a candidate gene for malignancies. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

CD81-AS1 (HGNC:49384): (CD81 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004356.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD81	NM_004356.4	MANE Select	c.40C>T	p.Leu14Phe	missense	Exon 1 of 8	NP_004347.1	P60033
	CD81	NM_001425135.1		c.40C>T	p.Leu14Phe	missense	Exon 1 of 8	NP_001412064.1
	CD81	NM_001425137.1		c.40C>T	p.Leu14Phe	missense	Exon 1 of 8	NP_001412066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD81	ENST00000263645.10	TSL:1 MANE Select	c.40C>T	p.Leu14Phe	missense	Exon 1 of 8	ENSP00000263645.5	P60033
	CD81-AS1	ENST00000427151.1	TSL:1	n.401G>A		non_coding_transcript_exon	Exon 1 of 3
	CD81	ENST00000905044.1		c.40C>T	p.Leu14Phe	missense	Exon 4 of 11	ENSP00000575103.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000204 AC: 4 AN: 196258 AF XY: 0.00000931

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000456

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1390956 Hom.: 0 Cov.: 29 AF XY: 0.00000290 AC XY: 2 AN XY: 690320

African (AFR) AF: 0.00 AC: 0 AN: 29170

American (AMR) AF: 0.00 AC: 0 AN: 38646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23946

East Asian (EAS) AF: 0.00 AC: 0 AN: 33914

South Asian (SAS) AF: 0.00 AC: 0 AN: 80018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5362

European-Non Finnish (NFE) AF: 0.00000465 AC: 5 AN: 1074424

Other (OTH) AF: 0.00 AC: 0 AN: 56448

GnomAD4 genome Cov.: 31

Alfa AF: 0.000102 Hom.: 0

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		2.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.77		Loss of stability (P = 0.0729)
MVP		0.87
MPC		1.6
ClinPred		0.94	D
GERP RS		2.5
PromoterAI		-0.089	Neutral
Varity_R		0.58
gMVP		0.57
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs759471923; hg19: chr11-2398819;