rs782280954

Variant names:

• chrX-155063978-T-G
• rs782280954
• NM_001018024.3:c.46A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001018024.3(CMC4):​c.46A>C​(p.Lys16Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000037 in 1,079,695 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000037 (0 hom. 3 hem.)
• Consequence: CMC4 NM_001018024.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18
• Publications: 3 publications found

Genes affected

CMC4 (HGNC:35428): (C-X9-C motif containing 4) This gene was identified by involvement in some t(X;14) translocations associated with mature T-cell proliferations. This region has a complex gene structure, with a common promoter and 5' exon spliced to two different sets of 3' exons that encode two different proteins. This gene represents the downstream 8 kDa protein that localizes to mitochondria.[provided by RefSeq, Mar 2009]

ENSG00000288258 (HGNC:):

MTCP1 (HGNC:7423): (mature T cell proliferation 1) This gene was identified by involvement in some t(X;14) translocations associated with mature T-cell proliferations. This region has a complex gene structure, with a common promoter and 5' exon spliced to two different sets of 3' exons that encode two different proteins. This gene represents the upstream 13 kDa protein that is a member of the TCL1 family. This protein may be involved in leukemogenesis. [provided by RefSeq, Mar 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29571843).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018024.3. 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
	CMC4	NM_001018024.3	MANE Select	c.46A>C	p.Lys16Gln	missense	Exon 2 of 3	NP_001018024.1	P56277-1
	MTCP1	NM_001018025.4	MANE Select	c.*1426A>C		downstream_gene	N/A	NP_001018025.1	P56278-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMC4	ENST00000369484.8	TSL:1 MANE Select	c.46A>C	p.Lys16Gln	missense	Exon 2 of 3	ENSP00000358496.3	P56277-1
	ENSG00000288258	ENST00000504061.1	TSL:3	n.*60A>C		non_coding_transcript_exon	Exon 2 of 3	ENSP00000427132.1	A0A0G2JKI4
	ENSG00000288258	ENST00000504061.1	TSL:3	n.*60A>C		3_prime_UTR	Exon 2 of 3	ENSP00000427132.1	A0A0G2JKI4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000123 AC: 2 AN: 163204 AF XY: 0.0000374

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: 0.0000262

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000370 AC: 4 AN: 1079695 Hom.: 0 Cov.: 27 AF XY: 0.00000854 AC XY: 3 AN XY: 351229

African (AFR) AF: 0.00 AC: 0 AN: 25273

American (AMR) AF: 0.00 AC: 0 AN: 29850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18848

East Asian (EAS) AF: 0.00 AC: 0 AN: 29646

South Asian (SAS) AF: 0.00 AC: 0 AN: 50197

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4085

European-Non Finnish (NFE) AF: 0.00000478 AC: 4 AN: 836145

Other (OTH) AF: 0.00 AC: 0 AN: 45307

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.84	T
PhyloP100		4.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.17	T
Sift4G	Uncertain	0.038	D
Polyphen		0.85	P
Vest4		0.36
MutPred		0.42		Loss of methylation at K16 (P = 5e-04)
MVP		0.28
MPC		1.2
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.26
gMVP		0.37
Mutation Taster		=99/1	polymorphism

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: rs782280954; hg19: chrX-154292253; COSMIC: COSV62899890; COSMIC: COSV62899890;