19-48607337-C-A

Variant names:

• chr19-48607337-C-A
• rs1321623728
• NM_133498.3:c.359C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_133498.3(SPACA4):​c.359C>A​(p.Pro120His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P120L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPACA4 NM_133498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

Genes affected

SPACA4 (HGNC:16441): (sperm acrosome associated 4) Predicted to be involved in cell adhesion. Predicted to be located in extracellular region and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM83E (HGNC:25972): (family with sequence similarity 83 member E) Enables protein kinase binding activity. Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04637879).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133498.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPACA4	NM_133498.3	MANE Select	c.359C>A	p.Pro120His	missense	Exon 1 of 1	NP_598005.1	Q8TDM5
	FAM83E	NM_017708.4	MANE Select	c.758+2539G>T		intron	N/A	NP_060178.2	Q2M2I3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPACA4	ENST00000321762.3	TSL:6 MANE Select	c.359C>A	p.Pro120His	missense	Exon 1 of 1	ENSP00000312774.1	Q8TDM5
	FAM83E	ENST00000263266.4	TSL:1 MANE Select	c.758+2539G>T		intron	N/A	ENSP00000263266.2	Q2M2I3
	FAM83E	ENST00000876133.1		c.758+2539G>T		intron	N/A	ENSP00000546192.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439026 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33104

American (AMR) AF: 0.00 AC: 0 AN: 41920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25572

East Asian (EAS) AF: 0.00 AC: 0 AN: 38680

South Asian (SAS) AF: 0.00 AC: 0 AN: 83578

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100146

Other (OTH) AF: 0.00 AC: 0 AN: 59398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.096
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.60	T
Polyphen		0.010	B
Vest4		0.16
MutPred		0.18		Loss of loop (P = 0.0203)
MVP		0.043
MPC		0.77
ClinPred		0.12	T
GERP RS		-0.067
Varity_R		0.13
gMVP		0.43
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1321623728; hg19: chr19-49110594;