Variant X-155063983-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001018024.3(CMC4):c.41T>C(p.Ile14Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000268 in 1,195,514 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000022 ( 0 hom. 9 hem. )

Consequence

CMC4
NM_001018024.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.75

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 -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMC4	NM_001018024.3 linkuse as main transcript	c.41T>C	p.Ile14Thr	missense_variant	2/3	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.41T>C	p.Ile14Thr	missense_variant	2/3	1	NM_001018024.3	ENSP00000358496.3	P56277-1
ENSG00000288258	ENST00000504061.1 linkuse as main transcript	n.*55T>C		non_coding_transcript_exon_variant	2/3	3		ENSP00000427132.1	A0A0G2JKI4
ENSG00000288258	ENST00000504061.1 linkuse as main transcript	n.*55T>C		3_prime_UTR_variant	2/3	3		ENSP00000427132.1	A0A0G2JKI4
CMC4	ENST00000369479.1 linkuse as main transcript	c.41T>C	p.Ile14Thr	missense_variant	2/3	3		ENSP00000358491.1	P56277-1

Frequencies

GnomAD3 genomes

AF:

0.0000710

AC:

AN:

112631

Hom.:

Cov.:

AF XY:

0.0000862

AC XY:

AN XY:

34795

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000276

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

GnomAD3 exomes

AF:

0.0000783

AC:

AN:

166111

Hom.:

AF XY:

0.0000719

AC XY:

AN XY:

55617

show subpopulations

Gnomad AFR exome

AF:

0.000558

Gnomad AMR exome

AF:

0.0000453

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000405

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000222

AC:

AN:

1082883

Hom.:

Cov.:

AF XY:

0.0000254

AC XY:

AN XY:

353721

show subpopulations

Gnomad4 AFR exome

AF:

0.000315

Gnomad4 AMR exome

AF:

0.0000658

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000368

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000239

Gnomad4 OTH exome

AF:

0.0000220

GnomAD4 genome

AF:

0.0000710

AC:

AN:

112631

Hom.:

Cov.:

AF XY:

0.0000862

AC XY:

AN XY:

34795

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000276

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

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 22, 2021

The c.41T>C (p.I14T) alteration is located in exon 2 (coding exon 1) of the CMC4 gene. This alteration results from a T to C substitution at nucleotide position 41, causing the isoleucine (I) at amino acid position 14 to be replaced by a threonine (T). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

.;D

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.40

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.98

D;D

Vest4

0.81

MVP

0.20

MPC

1.4

ClinPred

0.40

GERP RS

5.3

Varity_R

0.73

gMVP

0.49

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