Variant X-155061857-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001018024.3(CMC4):c.193T>C(p.Ser65Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,206,573 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CMC4
NM_001018024.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.425

Variant links:

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]

CMC4 links:

ENSG00000288258 (HGNC:):

ENSG00000288258 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034627974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMC4	NM_001018024.3 linkuse as main transcript	c.193T>C	p.Ser65Pro	missense_variant	3/3	ENST00000369484.8	NP_001018024.1	P56277-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CMC4	ENST00000369484.8 linkuse as main transcript	c.193T>C	p.Ser65Pro	missense_variant	3/3	1	NM_001018024.3	ENSP00000358496.3	P56277-1
ENSG00000288258	ENST00000504061.1 linkuse as main transcript	n.*207T>C		non_coding_transcript_exon_variant	3/3	3		ENSP00000427132.1	A0A0G2JKI4
ENSG00000288258	ENST00000504061.1 linkuse as main transcript	n.*207T>C		3_prime_UTR_variant	3/3	3		ENSP00000427132.1	A0A0G2JKI4
CMC4	ENST00000369479.1 linkuse as main transcript	c.193T>C	p.Ser65Pro	missense_variant	3/3	3		ENSP00000358491.1	P56277-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34512

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1094209

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359781

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.193T>C (p.S65P) alteration is located in exon 3 (coding exon 2) of the CMC4 gene. This alteration results from a T to C substitution at nucleotide position 193, causing the serine (S) at amino acid position 65 to be replaced by a proline (P). 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

0.057

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.85

CADD

Benign

9.7

DANN

Benign

0.92

DEOGEN2

Benign

0.027

T;T

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.29

.;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.030

N;N

REVEL

Benign

0.029

Sift

Benign

0.27

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0

B;B

Vest4

0.041

MutPred

0.42

Loss of phosphorylation at S65 (P = 0.0037);Loss of phosphorylation at S65 (P = 0.0037);

MVP

0.030

MPC

0.55

ClinPred

0.045

GERP RS

0.21

Varity_R

0.081

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over