9-154737-C-A

Position:

• chr9-154737-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018491.5(ZNG1A):​c.634G>T​(p.Asp212Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000519 in 1,598,276 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: ZNG1A NM_018491.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

Genes affected

ZNG1A (HGNC:17134): (Zn regulated GTPase metalloprotein activator 1A) Predicted to enable ATP binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNG1A (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.077653944).
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNG1A	NM_018491.5	c.634G>T	p.Asp212Tyr	missense_variant	8/15	ENST00000356521.9	NP_060961.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNG1A	ENST00000356521.9	c.634G>T	p.Asp212Tyr	missense_variant	8/15	1	NM_018491.5	ENSP00000348915.4
ZNG1A	ENST00000616803.4	n.*273G>T		non_coding_transcript_exon_variant	7/8	5		ENSP00000479698.1
ZNG1A	ENST00000616944.4	n.*179G>T		non_coding_transcript_exon_variant	9/14	2		ENSP00000482821.1
ZNG1A	ENST00000618361.4	n.*179G>T		non_coding_transcript_exon_variant	5/8	5		ENSP00000480295.1
ZNG1A	ENST00000619157.4	n.*179G>T		non_coding_transcript_exon_variant	5/12	5		ENSP00000483746.1
ZNG1A	ENST00000616803.4	n.*273G>T		3_prime_UTR_variant	7/8	5		ENSP00000479698.1
ZNG1A	ENST00000616944.4	n.*179G>T		3_prime_UTR_variant	9/14	2		ENSP00000482821.1
ZNG1A	ENST00000618361.4	n.*179G>T		3_prime_UTR_variant	5/8	5		ENSP00000480295.1
ZNG1A	ENST00000619157.4	n.*179G>T		3_prime_UTR_variant	5/12	5		ENSP00000483746.1
ZNG1A	ENST00000465014.6	n.*120+1744G>T		intron_variant		2		ENSP00000482298.1
ZNG1A	ENST00000612045.4	n.*260+1744G>T		intron_variant		1		ENSP00000477749.1
ZNG1A	ENST00000618061.4	n.*120+1744G>T		intron_variant		1		ENSP00000477647.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152182 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000193

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: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000260 AC: 62 AN: 238104 Hom.: 0 AF XY: 0.000239 AC XY: 31 AN XY: 129678

Gnomad AFR exome AF: 0.000447

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000850

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000544 AC: 786 AN: 1445976 Hom.: 3 Cov.: 30 AF XY: 0.000531 AC XY: 382 AN XY: 719796

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000511

Gnomad4 NFE exome AF: 0.000661

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152300 Hom.: 0 Cov.: 28 AF XY: 0.000215 AC XY: 16 AN XY: 74478

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000233 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000218 AC: 1

ExAC AF: 0.000235 AC: 28

EpiCase AF: 0.000709

EpiControl AF: 0.000415

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 23, 2024

The c.634G>T (p.D212Y) alteration is located in exon 8 (coding exon 8) of the CBWD1 gene. This alteration results from a G to T substitution at nucleotide position 634, causing the aspartic acid (D) at amino acid position 212 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	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.073	T;T;.;.;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M;M;.;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.91	P;P;P;P;.
Vest4		0.34
MVP		0.31
ClinPred		0.10	T
GERP RS		3.4
Varity_R		0.64
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs150673332; hg19: chr9-154737; COSMIC: COSV100071071;