Genetic Variant ZAN:p.Arg98His (chr7-100736848-G-A) – 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.293G>A(p.Arg98His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000789 in 1,482,388 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000081 ( 17 hom. )

Consequence

ZAN
NM_003386.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.12

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=0.074994236).

BS2

High Homozygotes in GnomAdExome4 at 17 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.293G>A	p.Arg98His	missense	Exon 5 of 48	NP_003377.2	Q9Y493-1
ZAN	NM_173059.3		c.293G>A	p.Arg98His	missense	Exon 5 of 46	NP_775082.2	Q9Y493-6
ZAN	NR_111917.2		n.489G>A		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.293G>A	p.Arg98His	missense	Exon 5 of 48	ENSP00000480750.1	Q9Y493-1
ZAN	ENST00000620596.4	TSL:1	c.293G>A	p.Arg98His	missense	Exon 5 of 46	ENSP00000481742.1	Q9Y493-6
ZAN	ENST00000538115.5	TSL:1	n.293G>A		non_coding_transcript_exon	Exon 5 of 47	ENSP00000445091.2	Q9Y493-4

Frequencies

GnomAD3 genomes

AF:

0.0000563

AC:

AN:

142162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000693

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000951

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000105

AC:

AN:

171312

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000754

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000149

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000144

Gnomad OTH exome

AF:

0.000216

GnomAD4 exome

AF:

0.0000813

AC:

109

AN:

1340226

Hom.:

Cov.:

AF XY:

0.0000799

AC XY:

AN XY:

663706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31418

American (AMR)

AF:

0.0000539

AC:

AN:

37078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24434

East Asian (EAS)

AF:

0.000163

AC:

AN:

36854

South Asian (SAS)

AF:

0.000125

AC:

AN:

79822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.0000840

AC:

AN:

1023998

Other (OTH)

AF:

0.0000897

AC:

AN:

55738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000563

AC:

AN:

142162

Hom.:

Cov.:

AF XY:

0.0000432

AC XY:

AN XY:

69486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39120

American (AMR)

AF:

0.0000693

AC:

AN:

14422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3356

East Asian (EAS)

AF:

0.00

AC:

AN:

4954

South Asian (SAS)

AF:

0.000218

AC:

AN:

4578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000951

AC:

AN:

63122

Other (OTH)

AF:

0.00

AC:

AN:

1958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000169

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000447

AC:

Asia WGS

AF:

0.000297

AC:

AN:

3380

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

0.080

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0070

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0085

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.43

M_CAP

Benign

0.0066

MetaRNN

Benign

0.075

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.96

PhyloP100

-4.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

REVEL

Benign

0.052

Sift4G

Uncertain

0.020

Polyphen

0.028

Vest4

0.14

MVP

0.048

MPC

0.41

ClinPred

0.17

GERP RS

-8.8

Varity_R

0.032

gMVP

0.75

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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