rs367593224

Variant names:

• chr7-100737347-G-A
• rs367593224
• NM_003386.3:c.611G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-100737347-G-A
• chr7-100737347-G-C
• chr7-100737347-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003386.3(ZAN):​c.611G>A​(p.Arg204His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,459,486 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000021 (2 hom.)
• Consequence: ZAN NM_003386.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08000627).
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAN	NM_003386.3	MANE Select	c.611G>A	p.Arg204His	missense splice_region	Exon 6 of 48	NP_003377.2	Q9Y493-1
	ZAN	NM_173059.3		c.611G>A	p.Arg204His	missense splice_region	Exon 6 of 46	NP_775082.2	Q9Y493-6
	ZAN	NR_111917.2		n.807G>A		splice_region non_coding_transcript_exon	Exon 6 of 48

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAN	ENST00000613979.5	TSL:1 MANE Select	c.611G>A	p.Arg204His	missense splice_region	Exon 6 of 48	ENSP00000480750.1	Q9Y493-1
	ZAN	ENST00000620596.4	TSL:1	c.611G>A	p.Arg204His	missense splice_region	Exon 6 of 46	ENSP00000481742.1	Q9Y493-6
	ZAN	ENST00000538115.5	TSL:1	n.611G>A		splice_region non_coding_transcript_exon	Exon 6 of 47	ENSP00000445091.2	Q9Y493-4

Frequencies

GnomAD3 genomes AF: 0.0000214 AC: 3 AN: 140276 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000160

Gnomad OTH AF: 0.000519

GnomAD2 exomes AF: 0.0000386 AC: 6 AN: 155510 AF XY: 0.0000482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000815

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 28 AN: 1319210 Hom.: 2 Cov.: 30 AF XY: 0.0000169 AC XY: 11 AN XY: 651390

African (AFR) AF: 0.0000325 AC: 1 AN: 30776

American (AMR) AF: 0.00 AC: 0 AN: 34598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23716

East Asian (EAS) AF: 0.00 AC: 0 AN: 36430

South Asian (SAS) AF: 0.00 AC: 0 AN: 77626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 0.0000267 AC: 27 AN: 1009368

Other (OTH) AF: 0.00 AC: 0 AN: 54788

GnomAD4 genome AF: 0.0000214 AC: 3 AN: 140276 Hom.: 0 Cov.: 26 AF XY: 0.0000146 AC XY: 1 AN XY: 68404

African (AFR) AF: 0.0000260 AC: 1 AN: 38428

American (AMR) AF: 0.00 AC: 0 AN: 14142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3330

East Asian (EAS) AF: 0.00 AC: 0 AN: 4888

South Asian (SAS) AF: 0.00 AC: 0 AN: 4552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000160 AC: 1 AN: 62622

Other (OTH) AF: 0.000519 AC: 1 AN: 1926

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000129 AC: 1

ExAC AF: 0.00000916 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.1
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.038
Sift4G	Uncertain	0.0040	D
Polyphen		0.15	B
Vest4		0.28
MVP		0.10
MPC		0.14
ClinPred		0.51	D
GERP RS		-6.1
Varity_R		0.028
gMVP		0.47
Mutation Taster		=279/21	polymorphism

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

Other links and lift over

dbSNP: rs367593224; hg19: chr7-100334970; COSMIC: COSV61817622;