Genetic Variant ZNG1F:p.Gln332His (chr9-41132313-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001085457.2(ZNG1F):c.996G>C(p.Gln332His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,604,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0000055 ( 1 hom. )

Consequence

ZNG1F
NM_001085457.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Variant links:

Genes affected

ZNG1F (HGNC:31978): (Zn regulated GTPase metalloprotein activator 1F) Predicted to enable ATP binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNG1F links:

FRG1HP (HGNC:51767): (FSHD region gene 1 family member H, pseudogene)

FRG1HP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNG1F	NM_001085457.2 link	c.996G>C	p.Gln332His	missense_variant	Exon 14 of 15	ENST00000377391.8	NP_001078926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNG1F	ENST00000377391.8 link	c.996G>C	p.Gln332His	missense_variant	Exon 14 of 15	1	NM_001085457.2	ENSP00000366608.4	Q4V339
ZNG1F	ENST00000456520.5 link	c.939G>C	p.Gln313His	missense_variant	Exon 13 of 14	1		ENSP00000401079.2	H0Y5V3
ZNG1F	ENST00000382436.7 link	n.*541G>C		non_coding_transcript_exon_variant	Exon 15 of 16	1		ENSP00000484049.1	A0A087X1C0
ZNG1F	ENST00000486387.6 link	n.*1561G>C		non_coding_transcript_exon_variant	Exon 16 of 17	2		ENSP00000480837.1	A0A0B4J2E3
ZNG1F	ENST00000382436.7 link	n.*541G>C		3_prime_UTR_variant	Exon 15 of 16	1		ENSP00000484049.1	A0A087X1C0
ZNG1F	ENST00000486387.6 link	n.*1561G>C		3_prime_UTR_variant	Exon 16 of 17	2		ENSP00000480837.1	A0A0B4J2E3

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

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

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

235458

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

127970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000173

Gnomad SAS 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:

0.00000550

AC:

AN:

1454458

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723586

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150412

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.996G>C (p.Q332H) alteration is located in exon 14 (coding exon 14) of the CBWD6 gene. This alteration results from a G to C substitution at nucleotide position 996, causing the glutamine (Q) at amino acid position 332 to be replaced by a histidine (H). 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

0.78

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

.;T;.

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Pathogenic

0.77

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.88

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over