4-15824942-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001775.4(CD38):c.425T>C(p.Met142Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD38 NM_001775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

Genes affected

CD38 (HGNC:1667): (CD38 molecule) The protein encoded by this gene is a non-lineage-restricted, type II transmembrane glycoprotein that synthesizes and hydrolyzes cyclic adenosine 5'-diphosphate-ribose, an intracellular calcium ion mobilizing messenger. The release of soluble protein and the ability of membrane-bound protein to become internalized indicate both extracellular and intracellular functions for the protein. This protein has an N-terminal cytoplasmic tail, a single membrane-spanning domain, and a C-terminal extracellular region with four N-glycosylation sites. Crystal structure analysis demonstrates that the functional molecule is a dimer, with the central portion containing the catalytic site. It is used as a prognostic marker for patients with chronic lymphocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD38	NM_001775.4	c.425T>C	p.Met142Thr	missense_variant	3/8	ENST00000226279.8
CD38	NR_132660.2	n.450+8302T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD38	ENST00000226279.8	c.425T>C	p.Met142Thr	missense_variant	3/8	1	NM_001775.4	P1
CD38	ENST00000502843.5	c.363+8302T>C		intron_variant, NMD_transcript_variant		1
CD38	ENST00000510674.1	c.107T>C	p.Met36Thr	missense_variant	2/6	5
CD38	ENST00000511430.1	n.528T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The c.425T>C (p.M142T) alteration is located in exon 3 (coding exon 3) of the CD38 gene. This alteration results from a T to C substitution at nucleotide position 425, causing the methionine (M) at amino acid position 142 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	Benign	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.25	B;.
Vest4		0.43
MutPred		0.76		Loss of catalytic residue at V138 (P = 0.0266);.;
MVP		0.58
MPC		0.43
ClinPred		0.47	T
GERP RS		4.2
Varity_R		0.47
gMVP		0.61

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

Other links and lift over

dbSNP: rs1560316530; hg19: chr4-15826565;