7-100737347-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003386.3(ZAN):​c.611G>T​(p.Arg204Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R204H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 26)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: ZAN NM_003386.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14548144).

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>T	p.Arg204Leu	missense splice_region	Exon 6 of 48	NP_003377.2	Q9Y493-1
	ZAN	NM_173059.3		c.611G>T	p.Arg204Leu	missense splice_region	Exon 6 of 46	NP_775082.2	Q9Y493-6
	ZAN	NR_111917.2		n.807G>T		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>T	p.Arg204Leu	missense splice_region	Exon 6 of 48	ENSP00000480750.1	Q9Y493-1
	ZAN	ENST00000620596.4	TSL:1	c.611G>T	p.Arg204Leu	missense splice_region	Exon 6 of 46	ENSP00000481742.1	Q9Y493-6
	ZAN	ENST00000538115.5	TSL:1	n.611G>T		splice_region non_coding_transcript_exon	Exon 6 of 47	ENSP00000445091.2	Q9Y493-4

Frequencies

GnomAD3 genomes AF: 0.00000713 AC: 1 AN: 140276 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000707

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000643 AC: 1 AN: 155510 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000423

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.58e-7 AC: 1 AN: 1319208 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 651390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30776

American (AMR) AF: 0.0000289 AC: 1 AN: 34598

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 36428

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: 0.00 AC: 0 AN: 1009368

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000712 AC: 1 AN: 140370 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 68506

African (AFR) AF: 0.00 AC: 0 AN: 38538

American (AMR) AF: 0.0000706 AC: 1 AN: 14160

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4876

South Asian (SAS) AF: 0.00 AC: 0 AN: 4538

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62614

Other (OTH) AF: 0.00 AC: 0 AN: 1948

ExAC AF: 0.00000916 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	1.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.1
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.15
Sift4G	Uncertain	0.0050	D
Polyphen		0.92	P
Vest4		0.43
MutPred		0.62		Loss of catalytic residue at R204 (P = 0.0094)
MVP		0.21
MPC		0.38
ClinPred		0.78	D
GERP RS		-6.1
Varity_R		0.086
gMVP		0.65
Mutation Taster		=297/3	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;