7-76397677-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080744.2(SSC4D):​c.709G>C​(p.Ala237Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SSC4D
NM_080744.2 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SSC4DNM_080744.2 linkc.709G>C p.Ala237Pro missense_variant Exon 6 of 11 ENST00000275560.4 NP_542782.1 Q8WTU2-1
SSC4DXM_024446664.2 linkc.796G>C p.Ala266Pro missense_variant Exon 7 of 12 XP_024302432.1
SSC4DXM_017011750.2 linkc.202G>C p.Ala68Pro missense_variant Exon 3 of 8 XP_016867239.1
ZP3NM_007155.6 linkc.-187C>G 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.709G>C p.Ala237Pro missense_variant Exon 6 of 11 1 NM_080744.2 ENSP00000275560.3 Q8WTU2-1
ZP3ENST00000336517 linkc.-187C>G 5_prime_UTR_variant Exon 1 of 9 1 ENSP00000337310.4 P21754-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 30, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.709G>C (p.A237P) alteration is located in exon 6 (coding exon 5) of the SSC4D gene. This alteration results from a G to C substitution at nucleotide position 709, causing the alanine (A) at amino acid position 237 to be replaced by a proline (P). 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
0.73
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.072
T
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.053
D
MetaRNN
Uncertain
0.53
D
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.8
L
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.8
D
REVEL
Benign
0.19
Sift
Uncertain
0.022
D
Sift4G
Uncertain
0.028
D
Polyphen
0.89
P
Vest4
0.50
MutPred
0.54
Gain of glycosylation at A237 (P = 0.0795);
MVP
0.65
MPC
1.4
ClinPred
0.93
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.71
gMVP
0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-76026994; API