chr8-81713971-C-A

Variant names:

• chr8-81713971-C-A
• rs770358468
• NM_024699.3:c.427G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024699.3(ZFAND1):​c.427G>T​(p.Val143Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V143I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ZFAND1 NM_024699.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

Genes affected

ZFAND1 (HGNC:25858): (zinc finger AN1-type containing 1) Enables proteasome binding activity. Involved in cellular response to arsenite ion; positive regulation of intracellular protein transport; and stress granule disassembly. Located in cytoplasmic stress granule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAND1	NM_024699.3	c.427G>T	p.Val143Phe	missense_variant	Exon 6 of 8	ENST00000220669.10	NP_078975.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFAND1	ENST00000220669.10	c.427G>T	p.Val143Phe	missense_variant	Exon 6 of 8	1	NM_024699.3	ENSP00000220669.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250006 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460428 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726472

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39572

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111638

Other (OTH) AF: 0.0000332 AC: 2 AN: 60328

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.427G>T (p.V143F) alteration is located in exon 6 (coding exon 6) of the ZFAND1 gene. This alteration results from a G to T substitution at nucleotide position 427, causing the valine (V) at amino acid position 143 to be replaced by a phenylalanine (F). 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	0.62
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;.;.;.;T;T;.;T;.;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D;D;D;D;.;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;.;.;M;.;.;.;.;.;.
PhyloP100		5.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;D;D;.;D;D;D;D
Polyphen		0.93	.;P;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.85
MutPred		0.54		Loss of MoRF binding (P = 0.0878);Loss of MoRF binding (P = 0.0878);.;.;.;.;.;Loss of MoRF binding (P = 0.0878);.;.;.;.;.;.;
MVP		0.26
MPC		0.19
ClinPred		0.86	D
GERP RS		5.7
Varity_R		0.73
gMVP		0.72
Mutation Taster		=19/81	disease causing

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

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Other links and lift over

dbSNP: rs770358468; hg19: chr8-82626206;