10-45616566-C-T

Variant names:

• chr10-45616566-C-T
• NM_174890.4:c.2054G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_174890.4(ZFAND4):​c.2054G>A​(p.Gly685Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFAND4 NM_174890.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53

Genes affected

ZFAND4 (HGNC:23504): (zinc finger AN1-type containing 4) Predicted to enable zinc ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAND4	NM_174890.4	c.2054G>A	p.Gly685Glu	missense_variant	Exon 10 of 10	ENST00000344646.10	NP_777550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFAND4	ENST00000344646.10	c.2054G>A	p.Gly685Glu	missense_variant	Exon 10 of 10	1	NM_174890.4	ENSP00000339484.5
ZFAND4	ENST00000374366.7	c.1832G>A	p.Gly611Glu	missense_variant	Exon 11 of 11	1		ENSP00000363486.3
ZFAND4	ENST00000374371	c.*21G>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000363491.1
ZFAND4	ENST00000374370.1	n.1774G>A		non_coding_transcript_exon_variant	Exon 7 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2054G>A (p.G685E) alteration is located in exon 10 (coding exon 9) of the ZFAND4 gene. This alteration results from a G to A substitution at nucleotide position 2054, causing the glycine (G) at amino acid position 685 to be replaced by a glutamic acid (E). 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	.;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.88	.;P
Vest4		0.79
MutPred		0.90		.;Loss of sheet (P = 0.0457);
MVP		0.70
MPC		0.26
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr10-46112014;