NM_080744.2:c.209G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_080744.2(SSC4D):c.209G>A(p.Arg70His) variant causes a missense change. The variant allele was found at a frequency of 0.0000138 in 1,517,478 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 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SSC4D
NM_080744.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.06

Publications

0 publications found

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]

SSC4D links:

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

ZP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSC4D	NM_080744.2 link	c.209G>A	p.Arg70His	missense_variant	Exon 4 of 11	ENST00000275560.4	NP_542782.1	Q8WTU2-1
SSC4D	XM_024446664.2 link	c.296G>A	p.Arg99His	missense_variant	Exon 5 of 12		XP_024302432.1
ZP3	NM_007155.6 link	c.-67+2755C>T		intron_variant	Intron 1 of 8		NP_009086.4	P21754-3
SSC4D	XM_017011750.2 link	c.-32-1755G>A		intron_variant	Intron 1 of 7		XP_016867239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSC4D	ENST00000275560.4 link	c.209G>A	p.Arg70His	missense_variant	Exon 4 of 11	1	NM_080744.2	ENSP00000275560.3		Q8WTU2-1
ZP3	ENST00000336517.8 link	c.-67+2755C>T		intron_variant	Intron 1 of 8	1		ENSP00000337310.4		P21754-3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000211

AC:

AN:

141976

AF XY:

0.0000256

show subpopulations

Gnomad AFR exome

AF:

0.000119

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1365244

Hom.:

Cov.:

AF XY:

0.0000119

AC XY:

AN XY:

669872

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

30070

American (AMR)

AF:

0.00

AC:

AN:

30662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22318

East Asian (EAS)

AF:

0.00

AC:

AN:

35462

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5192

European-Non Finnish (NFE)

AF:

0.0000113

AC:

AN:

1061718

Other (OTH)

AF:

0.0000179

AC:

AN:

55934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000172

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 10, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.209G>A (p.R70H) alteration is located in exon 4 (coding exon 3) of the SSC4D gene. This alteration results from a G to A substitution at nucleotide position 209, causing the arginine (R) at amino acid position 70 to be replaced by a histidine (H). 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

0.61

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.7

PhyloP100

6.1

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MVP

0.72

MPC

0.33

ClinPred

0.99

GERP RS

4.7

Varity_R

0.89

gMVP

0.71

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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NM_080744.2:c.209G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over