8-143250417-C-G

Position:

• chr8-143250417-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173832.6(ZFP41):​c.574C>G​(p.Arg192Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZFP41 NM_173832.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.151

Genes affected

ZFP41 (HGNC:26786): (ZFP41 zinc finger protein) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.05220017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFP41	NM_173832.6	c.574C>G	p.Arg192Gly	missense_variant	2/3	ENST00000330701.7
ZFP41	NM_001271156.3	c.574C>G	p.Arg192Gly	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFP41	ENST00000330701.7	c.574C>G	p.Arg192Gly	missense_variant	2/3	2	NM_173832.6	P1
ZFP41	ENST00000520584.6	c.574C>G	p.Arg192Gly	missense_variant	2/3	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459090 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725468

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 09, 2021

The c.574C>G (p.R192G) alteration is located in exon 2 (coding exon 1) of the ZFP41 gene. This alteration results from a C to G substitution at nucleotide position 574, causing the arginine (R) at amino acid position 192 to be replaced by a glycine (G). 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	0.43
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.036	N
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
REVEL	Benign	0.014
Sift4G	Uncertain	0.060	T;T;T
Vest4		0.13
MVP		0.14
MPC		0.12
ClinPred		0.21	T
GERP RS		-0.68

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: rs200699856; hg19: chr8-144332587;