10-45626094-T-G

Variant names:

• chr10-45626094-T-G
• rs139565989
• NM_174890.4:c.1729A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174890.4(ZFAND4):​c.1729A>C​(p.Thr577Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 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: 6.8e-7 (0 hom.)
• Consequence: ZFAND4 NM_174890.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.549

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06815547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAND4	NM_174890.4	c.1729A>C	p.Thr577Pro	missense_variant	Exon 7 of 10	ENST00000344646.10	NP_777550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFAND4	ENST00000344646.10	c.1729A>C	p.Thr577Pro	missense_variant	Exon 7 of 10	1	NM_174890.4	ENSP00000339484.5
ZFAND4	ENST00000374366.7	c.1507A>C	p.Thr503Pro	missense_variant	Exon 8 of 11	1		ENSP00000363486.3
ZFAND4	ENST00000374371.6	c.570-7834A>C		intron_variant	Intron 5 of 6	5		ENSP00000363491.1
ZFAND4	ENST00000374370.1	n.1449A>C		non_coding_transcript_exon_variant	Exon 4 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1729A>C (p.T577P) alteration is located in exon 7 (coding exon 6) of the ZFAND4 gene. This alteration results from a A to C substitution at nucleotide position 1729, causing the threonine (T) at amino acid position 577 to be replaced by a proline (P). 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	0.076
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.7
DANN	Benign	0.81
DEOGEN2	Benign	0.0016	.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.069
Sift	Benign	0.13	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.88	.;P
Vest4		0.088
MutPred		0.27		.;Loss of phosphorylation at T577 (P = 0.035);
MVP		0.21
MPC		0.065
ClinPred		0.12	T
GERP RS		-0.21
Varity_R		0.16
gMVP		0.20

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: rs139565989; hg19: chr10-46121542;