Genetic Variant ZAN:p.Thr165Ser (chr7-100737049-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003386.3(ZAN):c.494C>G(p.Thr165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,499,092 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000012 ( 2 hom. )

Consequence

ZAN
NM_003386.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.04

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17509776).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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	UniProt
ZAN	NM_003386.3	MANE Select	c.494C>G	p.Thr165Ser	missense	Exon 5 of 48	NP_003377.2	Q9Y493-1
ZAN	NM_173059.3		c.494C>G	p.Thr165Ser	missense	Exon 5 of 46	NP_775082.2	Q9Y493-6
ZAN	NR_111917.2		n.690C>G		non_coding_transcript_exon	Exon 5 of 48

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZAN	ENST00000613979.5	TSL:1 MANE Select	c.494C>G	p.Thr165Ser	missense	Exon 5 of 48	ENSP00000480750.1	Q9Y493-1
ZAN	ENST00000620596.4	TSL:1	c.494C>G	p.Thr165Ser	missense	Exon 5 of 46	ENSP00000481742.1	Q9Y493-6
ZAN	ENST00000538115.5	TSL:1	n.494C>G		non_coding_transcript_exon	Exon 5 of 47	ENSP00000445091.2	Q9Y493-4

Frequencies

GnomAD3 genomes

AF:

0.00000706

AC:

AN:

141550

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000256

AC:

AN:

194946

AF XY:

0.00000938

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000323

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1357542

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

673602

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31856

American (AMR)

AF:

0.00

AC:

AN:

39806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24594

East Asian (EAS)

AF:

0.000422

AC:

AN:

37926

South Asian (SAS)

AF:

0.00

AC:

AN:

81292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1032842

Other (OTH)

AF:

0.00

AC:

AN:

56362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.00000706

AC:

AN:

141550

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

69038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38892

American (AMR)

AF:

0.00

AC:

AN:

14302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3362

East Asian (EAS)

AF:

0.000203

AC:

AN:

4924

South Asian (SAS)

AF:

0.00

AC:

AN:

4580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62942

Other (OTH)

AF:

0.00

AC:

AN:

1948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000352

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.44

M_CAP

Benign

0.0077

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

2.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.0

REVEL

Benign

0.16

Sift4G

Pathogenic

0.0

Polyphen

0.94

Vest4

0.22

MutPred

0.67

Gain of MoRF binding (P = 0.1449)

MVP

0.13

MPC

0.38

ClinPred

0.55

GERP RS

4.1

Varity_R

0.11

gMVP

0.50

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over