13-32311562-C-A

Position:

• chr13-32311562-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136571.2(ZAR1L):​c.364G>T​(p.Asp122Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,382,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ZAR1L NM_001136571.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.322

Genes affected

ZAR1L (HGNC:37116): (zygote arrest 1 like) This gene encodes a member of the ZAR1 family that is predominantly expressed in oocytes and early embryos. The protein may function as an RNA regulator in early embryos. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09044248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZAR1L	NM_001136571.2	c.364G>T	p.Asp122Tyr	missense_variant	3/6	ENST00000533490.7	NP_001130043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZAR1L	ENST00000533490.7	c.364G>T	p.Asp122Tyr	missense_variant	3/6	5	NM_001136571.2	ENSP00000437289.2
ZAR1L	ENST00000345108.6	c.364G>T	p.Asp122Tyr	missense_variant	1/4	1		ENSP00000344616.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000434 AC: 6 AN: 1382094 Hom.: 0 Cov.: 32 AF XY: 0.00000588 AC XY: 4 AN XY: 680264

Gnomad4 AFR exome AF: 0.000161

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.364G>T (p.D122Y) alteration is located in exon 1 (coding exon 1) of the ZAR1L gene. This alteration results from a G to T substitution at nucleotide position 364, causing the aspartic acid (D) at amino acid position 122 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.72
DEOGEN2	Benign	0.0081	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.090	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.036
Sift	Benign	0.045	.;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.76	P;P
Vest4		0.13
MutPred		0.19		Gain of catalytic residue at P126 (P = 0.0173);Gain of catalytic residue at P126 (P = 0.0173);
MVP		0.099
ClinPred		0.17	T
GERP RS		-1.4
Varity_R		0.060
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2072213724; hg19: chr13-32885699;