rs314299

Variant names:

• chr7-100773850-C-T
• rs314299
• NM_003386.3:c.5764C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_003386.3(ZAN):​c.5764C>T​(p.His1922Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: ZAN NM_003386.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.828
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008918405).
• BP6: Variant 7-100773850-C-T is Benign according to our data. Variant chr7-100773850-C-T is described in ClinVar as [Benign]. Clinvar id is 403615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAN	NM_003386.3	c.5764C>T	p.His1922Tyr	missense_variant	Exon 31 of 48	ENST00000613979.5	NP_003377.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAN	ENST00000613979.5	c.5764C>T	p.His1922Tyr	missense_variant	Exon 31 of 48	1	NM_003386.3	ENSP00000480750.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.495 AC: 90251 AN: 182226 AF XY: 0.504

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.543

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.00000226 AC: 1 AN: 443222 Hom.: 0 Cov.: 0 AF XY: 0.00000454 AC XY: 1 AN XY: 220396

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22648

American (AMR) AF: 0.00 AC: 0 AN: 25768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9450

East Asian (EAS) AF: 0.00 AC: 0 AN: 37728

South Asian (SAS) AF: 0.00 AC: 0 AN: 33888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1190

European-Non Finnish (NFE) AF: 0.00000363 AC: 1 AN: 275330

Other (OTH) AF: 0.00 AC: 0 AN: 20150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

Alfa AF: 0.451 Hom.: 53107

ExAC AF: 0.469 AC: 45816

Asia WGS AF: 0.191 AC: 619 AN: 3230

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.43	.;.;T;T
MetaRNN	Benign	0.0089	T;T;T;T
PhyloP100		0.83
Sift4G	Uncertain	0.0020	D;D;D;D
Vest4		0.10
ClinPred		0.060	T
GERP RS		2.6
gMVP		0.71

Splicing

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

Other links and lift over

dbSNP: rs314299; hg19: chr7-100371473; COSMIC: COSV61804594;