7-76397688-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_080744.2(SSC4D):​c.698G>A​(p.Gly233Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SSC4D
NM_080744.2 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86
Variant links:
Genes affected
SSC4D (HGNC:14461): (scavenger receptor cysteine rich family member with 4 domains) The scavenger receptor cysteine-rich (SRCR) superfamily is an ancient and highly conserved group of cell surface and/or secreted proteins, some of which are involved in the development of the immune system and the regulation of both innate and adaptive immune responses. Group B SRCR domains usually contain 8 regularly spaced cysteines that give rise to a well-defined intradomain disulfide-bond pattern.[supplied by OMIM, Apr 2004]
ZP3 (HGNC:13189): (zona pellucida glycoprotein 3) The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The protein encoded by this gene is a structural component of the zona pellucida and functions in primary binding and induction of the sperm acrosome reaction. The nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a C-terminal consensus furin cleavage site, and a transmembrane domain. It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix. However, the requirement for furin cleavage in this process remains controversial based on mouse studies. A variation in the last exon of this gene has previously served as the basis for an additional ZP3 locus; however, sequence and literature review reveals that there is only one full-length ZP3 locus in the human genome. Another locus encoding a bipartite transcript designated POMZP3 contains a duplication of the last four exons of ZP3, including the above described variation, and maps closely to this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SSC4DNM_080744.2 linkc.698G>A p.Gly233Glu missense_variant Exon 6 of 11 ENST00000275560.4 NP_542782.1 Q8WTU2-1
SSC4DXM_024446664.2 linkc.785G>A p.Gly262Glu missense_variant Exon 7 of 12 XP_024302432.1
SSC4DXM_017011750.2 linkc.191G>A p.Gly64Glu missense_variant Exon 3 of 8 XP_016867239.1
ZP3NM_007155.6 linkc.-176C>T 5_prime_UTR_variant Exon 1 of 9 NP_009086.4 P21754-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SSC4DENST00000275560.4 linkc.698G>A p.Gly233Glu missense_variant Exon 6 of 11 1 NM_080744.2 ENSP00000275560.3 Q8WTU2-1
ZP3ENST00000336517 linkc.-176C>T 5_prime_UTR_variant Exon 1 of 9 1 ENSP00000337310.4 P21754-3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000407
AC:
1
AN:
245790
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133940
show subpopulations
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:
0.00000909
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461070
Hom.:
0
Cov.:
35
AF XY:
0.00000688
AC XY:
5
AN XY:
726918
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 16, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.698G>A (p.G233E) alteration is located in exon 6 (coding exon 5) of the SSC4D gene. This alteration results from a G to A substitution at nucleotide position 698, causing the glycine (G) at amino acid position 233 to be replaced by a glutamic acid (E). 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
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.43
T
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-7.3
D
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.77
Gain of solvent accessibility (P = 0.0411);
MVP
0.62
MPC
1.7
ClinPred
0.99
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.77
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs1209225118; hg19: chr7-76027005; API