rs314299

chr7-100773850-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1922C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: ZAN NM_003386.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.828

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 Benign. Variant got -10 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_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 19991 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAN	NM_003386.3	c.5764C>T	p.His1922Tyr	missense_variant	31/48	ENST00000613979.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAN	ENST00000613979.5	c.5764C>T	p.His1922Tyr	missense_variant	31/48	1	NM_003386.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.495 AC: 90251 AN: 182226 Hom.: 19991 AF XY: 0.504 AC XY: 50563 AN XY: 100388

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 SAS exome AF: 0.447

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

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: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.461 Hom.: 25584

ExAC AF: 0.469 AC: 45816

Asia WGS AF: 0.191 AC: 619 AN: 3230

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

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
MetaRNN	Benign	0.0089	T;T;T;T
MutationTaster	Benign	0.99	P;P;P;P
Sift4G	Uncertain	0.0020	D;D;D;D
Vest4		0.10
ClinPred		0.060	T
GERP RS		2.6
Varity_R		0.057
gMVP		0.71

Splicing

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

Publications

LitVar

Other links and lift over

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