9-121573-C-T

Variant names:

• chr9-121573-C-T
• rs777839409
• NM_018491.5:c.1082G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_018491.5(ZNG1A):​c.1082G>A​(p.Gly361Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000089 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNG1A NM_018491.5 missense, splice_region
• Scores: Splicing: ADA: 0.7743
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNG1A	NM_018491.5	c.1082G>A	p.Gly361Asp	missense_variant, splice_region_variant	Exon 15 of 15	ENST00000356521.9	NP_060961.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNG1A	ENST00000356521.9	c.1082G>A	p.Gly361Asp	missense_variant, splice_region_variant	Exon 15 of 15	1	NM_018491.5	ENSP00000348915.4
ZNG1A	ENST00000465014.6	n.*680G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 15 of 15	2		ENSP00000482298.1
ZNG1A	ENST00000612045.4	n.*803G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 16	1		ENSP00000477749.1
ZNG1A	ENST00000619157.4	n.*627G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 12	5		ENSP00000483746.1
ZNG1A	ENST00000465014.6	n.*680G>A		3_prime_UTR_variant	Exon 15 of 15	2		ENSP00000482298.1
ZNG1A	ENST00000612045.4	n.*803G>A		3_prime_UTR_variant	Exon 16 of 16	1		ENSP00000477749.1
ZNG1A	ENST00000619157.4	n.*627G>A		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000483746.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000447 AC: 11 AN: 246162 Hom.: 0 AF XY: 0.0000300 AC XY: 4 AN XY: 133344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000894 AC: 13 AN: 1454490 Hom.: 0 Cov.: 30 AF XY: 0.00000691 AC XY: 5 AN XY: 723708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000225

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000712 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1082G>A (p.G361D) alteration is located in exon 15 (coding exon 15) of the CBWD1 gene. This alteration results from a G to A substitution at nucleotide position 1082, causing the glycine (G) at amino acid position 361 to be replaced by an aspartic acid (D). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.9	H;H;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.8	D;.;D;.;D
REVEL	Uncertain	0.43
Sift	Benign	0.033	D;.;D;.;D
Sift4G	Uncertain	0.038	D;D;D;D;D
Polyphen		0.95	P;P;D;.;P
Vest4		0.93
MutPred		0.90		Gain of ubiquitination at K366 (P = 0.0805);Gain of ubiquitination at K366 (P = 0.0805);.;.;.;
MVP		0.77
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.65
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.14		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: rs777839409; hg19: chr9-121573;