15-68945952-A-G

Variant names:

• chr15-68945952-A-G
• rs1895950351
• NM_145658.4:c.418A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145658.4(SPESP1):​c.418A>G​(p.Ile140Val) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPESP1 NM_145658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.979

Genes affected

SPESP1 (HGNC:15570): (sperm equatorial segment protein 1) The encoded protein is a human alloantigen involved in sperm-egg binding and fusion. [provided by RefSeq, Apr 2010]

NOX5 (HGNC:):

ACMG classification

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=0.05822131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPESP1	NM_145658.4	c.418A>G	p.Ile140Val	missense_variant	Exon 2 of 2	ENST00000310673.4	NP_663633.1
SPESP1-NOX5	NM_001184780.2	c.29+15235A>G		intron_variant	Intron 1 of 15		NP_001171709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPESP1	ENST00000310673.4	c.418A>G	p.Ile140Val	missense_variant	Exon 2 of 2	1	NM_145658.4	ENSP00000312284.3
NOX5	ENST00000260364.9	c.-109+15235A>G		intron_variant	Intron 1 of 16	1		ENSP00000454143.1

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

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418A>G (p.I140V) alteration is located in exon 2 (coding exon 2) of the SPESP1 gene. This alteration results from a A to G substitution at nucleotide position 418, causing the isoleucine (I) at amino acid position 140 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.58
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.032
Sift	Benign	0.41	T
Sift4G	Benign	0.18	T
Polyphen		0.52	P
Vest4		0.15
MutPred		0.15		Gain of catalytic residue at I140 (P = 0.0644);
MVP		0.048
MPC		0.048
ClinPred		0.14	T
GERP RS		0.98
Varity_R		0.047
gMVP		0.046

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1895950351; hg19: chr15-69238291;