chr7-100738560-G-C

Position:

• chr7-100738560-G-C

Variant summary

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

The NM_003386.3(ZAN):​c.713G>C​(p.Gly238Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,374,722 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000022 (1 hom.)
• Consequence: ZAN NM_003386.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

ZAN (HGNC:12857): (zonadhesin) This gene encodes a protein that functions in the species specificity of sperm adhesion to the egg zona pellucida. The encoded protein is located in the acrosome and may be involved in signaling or gamete recognition. An allelic polymorphism in this gene results in both functional and frameshifted alleles; the reference genome represents the functional allele. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2015]

ACMG classification

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/exons	MANE	UniProt
ZAN	NM_003386.3	c.713G>C	p.Gly238Ala	missense_variant	7/48	ENST00000613979.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAN	ENST00000613979.5	c.713G>C	p.Gly238Ala	missense_variant	7/48	1	NM_003386.3	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1374722 Hom.: 1 Cov.: 31 AF XY: 0.00000293 AC XY: 2 AN XY: 683532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2023

The c.713G>C (p.G238A) alteration is located in exon 7 (coding exon 6) of the ZAN gene. This alteration results from a G to C substitution at nucleotide position 713, causing the glycine (G) at amino acid position 238 to be replaced by an alanine (A). 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	0.25
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.70	.;.;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.0	.;.;.;D
REVEL	Benign	0.21
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.40
MutPred		0.67		Loss of methylation at K236 (P = 0.0679);Loss of methylation at K236 (P = 0.0679);Loss of methylation at K236 (P = 0.0679);Loss of methylation at K236 (P = 0.0679);
MVP		0.38
MPC		0.43
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.10
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr7-100336183;