NM_001324144.2:c.1578T>A

Variant names:

• chrX-47448192-A-T
• rs148848609
• NM_001324144.2:c.1578T>A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001324144.2(ZNF41):​c.1578T>A​(p.Ala526Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,210,076 control chromosomes in the GnomAD database, including 9 homozygotes. There are 1,222 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., 99 hem., cov: 22)
  • Exomes 𝑓: 0.0032 (8 hom. 1123 hem.)
• Consequence: ZNF41 NM_001324144.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.24

Genes affected

ZNF41 (HGNC:13107): (zinc finger protein 41) This gene encodes a protein that contains KRAB-A and KRAB-B domains multiple zinc finger DNA binding motifs and finger linking regions characteristic of the Kruppel family. An initial study suggested that this gene may be associated with X-linked cognitive disability, but a later study has called this finding into question (PMID:23871722).[provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-47448192-A-T is Benign according to our data. Variant chrX-47448192-A-T is described in ClinVar as [Benign]. Clinvar id is 368363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47448192-A-T is described in Lovd as [Benign]. Variant chrX-47448192-A-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.24 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 99 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF41	NM_001324144.2	c.1578T>A	p.Ala526Ala	synonymous_variant	Exon 5 of 5	ENST00000684689.1	NP_001311073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF41	ENST00000684689.1	c.1578T>A	p.Ala526Ala	synonymous_variant	Exon 5 of 5		NM_001324144.2	ENSP00000508254.1
ZNF41	ENST00000313116.11	c.1578T>A	p.Ala526Ala	synonymous_variant	Exon 5 of 5	1		ENSP00000315173.7
ZNF41	ENST00000377065.8	c.1578T>A	p.Ala526Ala	synonymous_variant	Exon 5 of 5	1		ENSP00000366265.4

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 302 AN: 111812 Hom.: 1 Cov.: 22 AF XY: 0.00291 AC XY: 99 AN XY: 33984

Gnomad AFR AF: 0.000358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00795

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00421

Gnomad OTH AF: 0.00466

GnomAD3 exomes AF: 0.00246 AC: 452 AN: 183441 Hom.: 1 AF XY: 0.00236 AC XY: 160 AN XY: 67895

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000668

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00694

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00320 AC: 3513 AN: 1098209 Hom.: 8 Cov.: 32 AF XY: 0.00309 AC XY: 1123 AN XY: 363567

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.000464

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000923

Gnomad4 FIN exome AF: 0.00735

Gnomad4 NFE exome AF: 0.00359

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00270 AC: 302 AN: 111867 Hom.: 1 Cov.: 22 AF XY: 0.00291 AC XY: 99 AN XY: 34049

Gnomad4 AFR AF: 0.000357

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00795

Gnomad4 NFE AF: 0.00421

Gnomad4 OTH AF: 0.00460

Alfa AF: 0.00480 Hom.: 36

Bravo AF: 0.00181

EpiCase AF: 0.00256

EpiControl AF: 0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 22, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.58

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: rs148848609; hg19: chrX-47307591;