X-48008414-G-A

Position:

• chrX-48008414-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001394298.1(SPACA5):​c.184G>A​(p.Ala62Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SPACA5 NM_001394298.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.245

Genes affected

SPACA5 (HGNC:31353): (sperm acrosome associated 5) Predicted to enable lysozyme activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ZNF630 (HGNC:28855): (zinc finger protein 630) This gene encodes a protein containing an N-terminal Kruppel-associated box-containing (KRAB) domain and 13 Kruppel-type C2H2 zinc finger domains. This gene resides on an area of chromosome X that has been implicated in nonsyndromic X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039892763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPACA5	NM_001394298.1	c.184G>A	p.Ala62Thr	missense_variant	2/4	ENST00000376940.4	NP_001381227.1
SPACA5	NM_205856.3	c.184G>A	p.Ala62Thr	missense_variant	3/5		NP_995328.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPACA5	ENST00000376940.4	c.184G>A	p.Ala62Thr	missense_variant	2/4	1	NM_001394298.1	ENSP00000366139	P1
SPACA5	ENST00000304355.9	c.184G>A	p.Ala62Thr	missense_variant	3/5	1		ENSP00000305847	P1
ZNF630	ENST00000428463.5	c.*417-4712C>T		intron_variant, NMD_transcript_variant		2		ENSP00000400030

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

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

Apr 13, 2022

The c.184G>A (p.A62T) alteration is located in exon 3 (coding exon 2) of the SPACA5 gene. This alteration results from a G to A substitution at nucleotide position 184, causing the alanine (A) at amino acid position 62 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
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.014	T;T
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.035
Sift	Benign	0.53	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0010	B;B
Vest4		0.035
MutPred		0.28		Loss of stability (P = 0.0318);Loss of stability (P = 0.0318);
MVP		0.37
ClinPred		0.0021	T
GERP RS		0.83
Varity_R		0.052
gMVP		0.064

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: rs1556902947; hg19: chrX-47867812; COSMIC: COSV58560278; COSMIC: COSV58560278;