4-15834300-A-G

Position:

• chr4-15834300-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000226279.8(CD38):​c.583A>G​(p.Arg195Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD38 ENST00000226279.8 missense, splice_region
• Scores: Splicing: ADA: 0.001116
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.568

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39933804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD38	NM_001775.4	c.583A>G	p.Arg195Gly	missense_variant, splice_region_variant	4/8	ENST00000226279.8	NP_001766.2
CD38	NR_132660.2	n.534A>G		splice_region_variant, non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD38	ENST00000226279.8	c.583A>G	p.Arg195Gly	missense_variant, splice_region_variant	4/8	1	NM_001775.4	ENSP00000226279	P1
CD38	ENST00000502843.5	c.*78A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	3/7	1		ENSP00000427277
CD38	ENST00000510674.1	c.247A>G	p.Arg83Gly	missense_variant, splice_region_variant	3/6	5		ENSP00000423047

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449094 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 721808

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Oct 26, 2022

The c.583A>G (p.R195G) alteration is located in exon 4 (coding exon 4) of the CD38 gene. This alteration results from a A to G substitution at nucleotide position 583, causing the arginine (R) at amino acid position 195 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.84	P;.
Vest4		0.28
MutPred		0.62		Loss of stability (P = 0.0238);.;
MVP		0.64
MPC		0.53
ClinPred		0.68	D
GERP RS		2.8
Varity_R		0.47
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-15835923;