X-47447899-G-A

Variant names:

• chrX-47447899-G-A
• rs866998933
• NM_001324144.2:c.1871C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001324144.2(ZNF41):​c.1871C>T​(p.Ala624Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000513 in 1,209,575 control chromosomes in the GnomAD database, including 2 homozygotes. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A624A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000055 (2 hom. 17 hem.)
• Consequence: ZNF41 NM_001324144.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.33
• Publications: 2 publications found

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]

ZNF41 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08811453).
• BS2: High Homozygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324144.2. 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
	ZNF41	NM_001324144.2	MANE Select	c.1871C>T	p.Ala624Val	missense	Exon 5 of 5	NP_001311073.1	P51814-6
	ZNF41	NM_001324155.1		c.1997C>T	p.Ala666Val	missense	Exon 4 of 4	NP_001311084.1	P51814-1
	ZNF41	NM_001324154.1		c.1973C>T	p.Ala658Val	missense	Exon 4 of 4	NP_001311083.1	P51814-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF41	ENST00000684689.1	MANE Select	c.1871C>T	p.Ala624Val	missense	Exon 5 of 5	ENSP00000508254.1	P51814-6
	ZNF41	ENST00000313116.11	TSL:1	c.1871C>T	p.Ala624Val	missense	Exon 5 of 5	ENSP00000315173.7	P51814-6
	ZNF41	ENST00000377065.8	TSL:1	c.1871C>T	p.Ala624Val	missense	Exon 5 of 5	ENSP00000366265.4	P51814-6

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111366 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183380 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000546 AC: 60 AN: 1098209 Hom.: 2 Cov.: 32 AF XY: 0.0000468 AC XY: 17 AN XY: 363567

African (AFR) AF: 0.000265 AC: 7 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00557 AC: 23 AN: 4127

European-Non Finnish (NFE) AF: 0.0000356 AC: 30 AN: 842122

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111366 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33616

African (AFR) AF: 0.0000653 AC: 2 AN: 30640

American (AMR) AF: 0.00 AC: 0 AN: 10421

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53059

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	15
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.99	T
PhyloP100		-2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.040
Sift	Benign	0.55	T
Sift4G	Benign	0.50	T
Polyphen		0.71	P
Vest4		0.072
MVP		0.56
MPC		0.88
ClinPred		0.13	T
GERP RS		1.9
gMVP		0.061
Mutation Taster		=99/1	polymorphism

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: rs866998933; hg19: chrX-47307298; COSMIC: COSV57446089; COSMIC: COSV57446089;