8-112237296-G-T

Position:

• chr8-112237296-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198123.2(CSMD3):​c.10521C>A​(p.Phe3507Leu) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F3507S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSMD3 NM_198123.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

Genes affected

CSMD3 (HGNC:19291): (CUB and Sushi multiple domains 3) Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17879081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSMD3	NM_198123.2	c.10521C>A	p.Phe3507Leu	missense_variant	67/71	ENST00000297405.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSMD3	ENST00000297405.10	c.10521C>A	p.Phe3507Leu	missense_variant	67/71	1	NM_198123.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 19, 2024

The c.10521C>A (p.F3507L) alteration is located in exon 67 (coding exon 67) of the CSMD3 gene. This alteration results from a C to A substitution at nucleotide position 10521, causing the phenylalanine (F) at amino acid position 3507 to be replaced by a leucine (L). 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	0.75
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	.;N;.;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D;T;D;T
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.014	B;B;.;B
Vest4		0.57
MutPred		0.40		.;Loss of methylation at K3508 (P = 0.0275);.;.;
MVP		0.25
MPC		0.19
ClinPred		0.96	D
GERP RS		0.65
Varity_R		0.32
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-113249525;