9-123243-G-A

Position:

• chr9-123243-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018491.5(ZNG1A):​c.925C>T​(p.His309Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNG1A NM_018491.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0790

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07781586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNG1A	NM_018491.5	c.925C>T	p.His309Tyr	missense_variant	13/15	ENST00000356521.9	NP_060961.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNG1A	ENST00000356521.9	c.925C>T	p.His309Tyr	missense_variant	13/15	1	NM_018491.5	ENSP00000348915.4
ZNG1A	ENST00000465014.6	n.*523C>T		non_coding_transcript_exon_variant	13/15	2		ENSP00000482298.1
ZNG1A	ENST00000612045.4	n.*646C>T		non_coding_transcript_exon_variant	14/16	1		ENSP00000477749.1
ZNG1A	ENST00000616944.4	n.*470C>T		non_coding_transcript_exon_variant	14/14	2		ENSP00000482821.1
ZNG1A	ENST00000619157.4	n.*470C>T		non_coding_transcript_exon_variant	10/12	5		ENSP00000483746.1
ZNG1A	ENST00000465014.6	n.*523C>T		3_prime_UTR_variant	13/15	2		ENSP00000482298.1
ZNG1A	ENST00000612045.4	n.*646C>T		3_prime_UTR_variant	14/16	1		ENSP00000477749.1
ZNG1A	ENST00000616944.4	n.*470C>T		3_prime_UTR_variant	14/14	2		ENSP00000482821.1
ZNG1A	ENST00000619157.4	n.*470C>T		3_prime_UTR_variant	10/12	5		ENSP00000483746.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 28 AN: 127962 Hom.: 0 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.000785

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: 0.0000168

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000232 AC: 1 AN: 43034 Hom.: 0 AF XY: 0.0000440 AC XY: 1 AN XY: 22730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000258 AC: 35 AN: 1354102 Hom.: 0 Cov.: 24 AF XY: 0.0000267 AC XY: 18 AN XY: 675174

Gnomad4 AFR exome AF: 0.000452

Gnomad4 AMR exome AF: 0.0000235

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: 0.0000154

Gnomad4 OTH exome AF: 0.0000703

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000219 AC: 28 AN: 128084 Hom.: 0 Cov.: 19 AF XY: 0.000163 AC XY: 10 AN XY: 61412

Gnomad4 AFR AF: 0.000782

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: 0.0000168

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

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

Sep 25, 2023

The c.925C>T (p.H309Y) alteration is located in exon 13 (coding exon 13) of the CBWD1 gene. This alteration results from a C to T substitution at nucleotide position 925, causing the histidine (H) at amino acid position 309 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	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T;T;.;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.70	.;T;T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L;L;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N;.;N;.;N
REVEL	Benign	0.049
Sift	Benign	0.034	D;.;D;.;D
Sift4G	Uncertain	0.042	D;D;D;D;D
Polyphen		0.024	B;B;B;.;B
Vest4		0.14
MutPred		0.46		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;.;.;
MVP		0.35
ClinPred		0.090	T
GERP RS		2.3
Varity_R		0.059
gMVP		0.013

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: rs982586780; hg19: chr9-123243;