8-81717251-C-T

Position:

• chr8-81717251-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024699.3(ZFAND1):​c.136G>A​(p.Glu46Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 33)
• Consequence: ZFAND1 NM_024699.3 missense, splice_region
• Scores: Splicing: ADA: 0.6334
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.77

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37891304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFAND1	NM_024699.3	c.136G>A	p.Glu46Lys	missense_variant, splice_region_variant	3/8	ENST00000220669.10	NP_078975.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFAND1	ENST00000220669.10	c.136G>A	p.Glu46Lys	missense_variant, splice_region_variant	3/8	1	NM_024699.3	ENSP00000220669	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Jan 30, 2024

The c.136G>A (p.E46K) alteration is located in exon 3 (coding exon 3) of the ZFAND1 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glutamic acid (E) at amino acid position 46 to be replaced by a lysine (K). 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	0.070
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	.;T;.
Eigen	Benign	-0.083
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.13	.;B;.
Vest4		0.54
MutPred		0.48		Gain of methylation at E46 (P = 0.0037);Gain of methylation at E46 (P = 0.0037);Gain of methylation at E46 (P = 0.0037);
MVP		0.62
MPC		0.038
ClinPred		0.63	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.54
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-82629486;