15-68945634-A-G

Variant names:

• chr15-68945634-A-G
• rs1420325883
• NM_145658.4:c.100A>G

Variant summary

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

The NM_145658.4(SPESP1):​c.100A>G​(p.Asn34Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,435,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPESP1 NM_145658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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 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=0.36695427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPESP1	NM_145658.4	c.100A>G	p.Asn34Asp	missense_variant	Exon 2 of 2	ENST00000310673.4	NP_663633.1
SPESP1-NOX5	NM_001184780.2	c.29+14917A>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.100A>G	p.Asn34Asp	missense_variant	Exon 2 of 2	1	NM_145658.4	ENSP00000312284.3
NOX5	ENST00000260364.9	c.-109+14917A>G		intron_variant	Intron 1 of 16	1		ENSP00000454143.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000442 AC: 1 AN: 226472 Hom.: 0 AF XY: 0.00000815 AC XY: 1 AN XY: 122688

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000938

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1435072 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 712886

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: 0.00000272

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

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100A>G (p.N34D) 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 100, causing the asparagine (N) at amino acid position 34 to be replaced by an aspartic acid (D). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.10
Sift	Benign	0.042	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.27		Gain of phosphorylation at Y36 (P = 0.0715);
MVP		0.32
MPC		0.31
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.35
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs1420325883; hg19: chr15-69237973;