19-48607028-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_133498.3(SPACA4):​c.50C>T​(p.Thr17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,611,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SPACA4
NM_133498.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.407
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.06791744).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPACA4NM_133498.3 linkc.50C>T p.Thr17Met missense_variant Exon 1 of 1 ENST00000321762.3 NP_598005.1 Q8TDM5A0A140VJU1
FAM83ENM_017708.4 linkc.758+2848G>A intron_variant Intron 5 of 6 ENST00000263266.4 NP_060178.2 Q2M2I3
FAM83EXM_024451561.2 linkc.758+2848G>A intron_variant Intron 5 of 6 XP_024307329.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPACA4ENST00000321762.3 linkc.50C>T p.Thr17Met missense_variant Exon 1 of 1 6 NM_133498.3 ENSP00000312774.1 Q8TDM5
FAM83EENST00000263266.4 linkc.758+2848G>A intron_variant Intron 5 of 6 1 NM_017708.4 ENSP00000263266.2 Q2M2I3

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000482
AC:
12
AN:
248834
Hom.:
0
AF XY:
0.0000519
AC XY:
7
AN XY:
134992
show subpopulations
Gnomad AFR exome
AF:
0.000186
Gnomad AMR exome
AF:
0.0000289
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:
0.0000708
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000112
AC:
163
AN:
1459346
Hom.:
0
Cov.:
31
AF XY:
0.0000992
AC XY:
72
AN XY:
726136
show subpopulations
Gnomad4 AFR exome
AF:
0.000358
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000125
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152358
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000162
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 01, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.50C>T (p.T17M) alteration is located in exon 1 (coding exon 1) of the SPACA4 gene. This alteration results from a C to T substitution at nucleotide position 50, causing the threonine (T) at amino acid position 17 to be replaced by a methionine (M). 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
0.10
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
12
DANN
Benign
0.69
DEOGEN2
Benign
0.016
T
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.47
T
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.068
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
2.0
M
PrimateAI
Benign
0.41
T
PROVEAN
Benign
0.43
N
REVEL
Benign
0.058
Sift
Uncertain
0.0090
D
Sift4G
Benign
0.12
T
Polyphen
0.93
P
Vest4
0.23
MVP
0.043
MPC
1.7
ClinPred
0.047
T
GERP RS
2.0
Varity_R
0.020
gMVP
0.51

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143767613; hg19: chr19-49110285; COSMIC: COSV54370664; COSMIC: COSV54370664; API