9-41133718-C-T

Variant names:

• chr9-41133718-C-T
• rs373196176
• NM_001085457.2:c.841G>A

Variant summary

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

The NM_001085457.2(ZNG1F):​c.841G>A​(p.Val281Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 151,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000066 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNG1F NM_001085457.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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]

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09296885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNG1F	NM_001085457.2	c.841G>A	p.Val281Ile	missense_variant	Exon 12 of 15	ENST00000377391.8	NP_001078926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNG1F	ENST00000377391.8	c.841G>A	p.Val281Ile	missense_variant	Exon 12 of 15	1	NM_001085457.2	ENSP00000366608.4
ZNG1F	ENST00000456520.5	c.784G>A	p.Val262Ile	missense_variant	Exon 11 of 14	1		ENSP00000401079.2
ZNG1F	ENST00000382436.7	n.*386G>A		non_coding_transcript_exon_variant	Exon 13 of 16	1		ENSP00000484049.1
ZNG1F	ENST00000486387.6	n.*1406G>A		non_coding_transcript_exon_variant	Exon 14 of 17	2		ENSP00000480837.1
ZNG1F	ENST00000382436.7	n.*386G>A		3_prime_UTR_variant	Exon 13 of 16	1		ENSP00000484049.1
ZNG1F	ENST00000486387.6	n.*1406G>A		3_prime_UTR_variant	Exon 14 of 17	2		ENSP00000480837.1

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 39 AN: 150920 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000707

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000984

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000665 AC: 96 AN: 1444080 Hom.: 0 Cov.: 41 AF XY: 0.0000807 AC XY: 58 AN XY: 718800

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000581

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000833

GnomAD4 genome AF: 0.000258 AC: 39 AN: 151042 Hom.: 0 Cov.: 28 AF XY: 0.000203 AC XY: 15 AN XY: 73790

Gnomad4 AFR AF: 0.000705

Gnomad4 AMR AF: 0.0000663

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000986

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841G>A (p.V281I) alteration is located in exon 12 (coding exon 12) of the CBWD6 gene. This alteration results from a G to A substitution at nucleotide position 841, causing the valine (V) at amino acid position 281 to be replaced by an isoleucine (I). 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	0.082
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.00096	.;T;.
LIST_S2	Benign	0.85	D;D;D
MetaRNN	Benign	0.093	T;T;T
Sift4G	Benign	0.39	T;T;T
Vest4		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.22

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: rs373196176; hg19: chr9-70912520;