Genetic Variant NM_003386.3:c.5649G>T (chr7-100773735-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

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

The NM_003386.3(ZAN):c.5649G>T(p.Trp1883Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. W1883R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ZAN
NM_003386.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.90

Publications

0 publications found

Variant links:

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]

ZAN links:

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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, 0.852

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003386.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZAN	NM_003386.3	MANE Select	c.5649G>T	p.Trp1883Cys	missense	Exon 31 of 48	NP_003377.2
ZAN	NM_173059.3		c.5649G>T	p.Trp1883Cys	missense	Exon 31 of 46	NP_775082.2
ZAN	NR_111917.2		n.5845G>T		non_coding_transcript_exon	Exon 31 of 48

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZAN	ENST00000613979.5	TSL:1 MANE Select	c.5649G>T	p.Trp1883Cys	missense	Exon 31 of 48	ENSP00000480750.1
ZAN	ENST00000620596.4	TSL:1	c.5649G>T	p.Trp1883Cys	missense	Exon 31 of 46	ENSP00000481742.1
ZAN	ENST00000538115.5	TSL:1	n.5649G>T		non_coding_transcript_exon	Exon 31 of 47	ENSP00000445091.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457714

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

43994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25988

East Asian (EAS)

AF:

0.00

AC:

AN:

39542

South Asian (SAS)

AF:

0.00

AC:

AN:

85438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110248

Other (OTH)

AF:

0.00

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.70

MutationAssessor

Pathogenic

3.3

PhyloP100

4.9

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-10

REVEL

Uncertain

0.33

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.63

MutPred

0.63

Gain of disorder (P = 0.0254)

MVP

0.14

MPC

0.11

ClinPred

1.0

GERP RS

4.4

Varity_R

0.37

gMVP

0.97

Mutation Taster

=52/48

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over