chr10-45618159-C-T

Variant names:

• chr10-45618159-C-T
• rs199863028
• NM_174890.4:c.2029G>A

Variant summary

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

The NM_174890.4(ZFAND4):​c.2029G>A​(p.Ala677Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A677S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZFAND4 NM_174890.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.44
• Publications: 0 publications found

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

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, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174890.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFAND4	NM_174890.4	MANE Select	c.2029G>A	p.Ala677Thr	missense	Exon 9 of 10	NP_777550.2	Q86XD8
	ZFAND4	NM_001128324.2		c.2029G>A	p.Ala677Thr	missense	Exon 9 of 10	NP_001121796.1	Q86XD8
	ZFAND4	NM_001282905.1		c.1807G>A	p.Ala603Thr	missense	Exon 10 of 11	NP_001269834.1	J3KPC0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFAND4	ENST00000344646.10	TSL:1 MANE Select	c.2029G>A	p.Ala677Thr	missense	Exon 9 of 10	ENSP00000339484.5	Q86XD8
	ZFAND4	ENST00000374366.7	TSL:1	c.1807G>A	p.Ala603Thr	missense	Exon 10 of 11	ENSP00000363486.3	J3KPC0
	ZFAND4	ENST00000947494.1		c.2047G>A	p.Ala683Thr	missense	Exon 9 of 10	ENSP00000617553.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460816 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726704

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111670

Other (OTH) AF: 0.00 AC: 0 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.19
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.015	D
Polyphen		0.066	B
Vest4		0.72
MutPred		0.65		Gain of sheet (P = 0.0101)
MVP		0.56
MPC		0.16
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.37
gMVP		0.51
Mutation Taster		=36/64	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

Other links and lift over

dbSNP: rs199863028; hg19: chr10-46113607;