NM_080744.2:c.791G>C

Variant names:

• chr7-76397595-C-G
• rs940223572
• NM_080744.2:c.791G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_080744.2(SSC4D):​c.791G>C​(p.Arg264Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R264L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SSC4D NM_080744.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655
• Publications: 0 publications found

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]

ZP3 Gene-Disease associations (from GenCC):

• oocyte maturation defect 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• female infertility due to zona pellucida defect

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• inherited oocyte maturation defect

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
SSC4D	NM_080744.2	c.791G>C	p.Arg264Pro	missense_variant	Exon 6 of 11	ENST00000275560.4	NP_542782.1
SSC4D	XM_024446664.2	c.878G>C	p.Arg293Pro	missense_variant	Exon 7 of 12		XP_024302432.1
SSC4D	XM_017011750.2	c.284G>C	p.Arg95Pro	missense_variant	Exon 3 of 8		XP_016867239.1
ZP3	NM_007155.6	c.-269C>G		5_prime_UTR_variant	Exon 1 of 9		NP_009086.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSC4D	ENST00000275560.4	c.791G>C	p.Arg264Pro	missense_variant	Exon 6 of 11	1	NM_080744.2	ENSP00000275560.3
ZP3	ENST00000336517.8	c.-269C>G		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000337310.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.66
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.64	P
Vest4		0.60
MutPred		0.52		Gain of catalytic residue at P263 (P = 0.0133);
MVP		0.35
MPC		1.6
ClinPred		0.82	D
GERP RS		1.2
PromoterAI		-0.22	Neutral
Varity_R		0.33
gMVP		0.77
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs940223572; hg19: chr7-76026912;