Genetic Variant ZFAND4:p.Ala638Ser (chr10-45624598-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_174890.4(ZFAND4):c.1912G>T(p.Ala638Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ZFAND4
NM_174890.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0200

Variant links:

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]

ZFAND4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042438835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAND4	NM_174890.4 link	c.1912G>T	p.Ala638Ser	missense_variant	Exon 8 of 10	ENST00000344646.10	NP_777550.2	Q86XD8A0A024R7V9Q86WR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZFAND4	ENST00000344646.10 link	c.1912G>T	p.Ala638Ser	missense_variant	Exon 8 of 10	1	NM_174890.4	ENSP00000339484.5	Q86XD8
ZFAND4	ENST00000374366.7 link	c.1690G>T	p.Ala564Ser	missense_variant	Exon 9 of 11	1		ENSP00000363486.3	J3KPC0
ZFAND4	ENST00000374371.6 link	c.570-6338G>T		intron_variant	Intron 5 of 6	5		ENSP00000363491.1	Q5VVY4
ZFAND4	ENST00000374370.1 link	n.1632G>T		non_coding_transcript_exon_variant	Exon 5 of 7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251292

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000342

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1912G>T (p.A638S) alteration is located in exon 8 (coding exon 7) of the ZFAND4 gene. This alteration results from a G to T substitution at nucleotide position 1912, causing the alanine (A) at amino acid position 638 to be replaced by a serine (S). 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

0.084

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.4

DANN

Benign

0.69

DEOGEN2

Benign

0.00056

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.0096

MetaRNN

Benign

0.042

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;L

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.32

N;N

REVEL

Benign

0.022

Sift

Benign

0.52

T;T

Sift4G

Benign

0.81

T;T

Polyphen

0.0010

.;B

Vest4

0.16

MutPred

0.26

.;Gain of glycosylation at A638 (P = 0.0154);

MVP

0.085

MPC

0.030

ClinPred

0.031

GERP RS

0.35

Varity_R

0.043

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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