X-47447899-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001324144.2(ZNF41):​c.1871C>G​(p.Ala624Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,209,575 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. 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. A624V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: ZNF41 NM_001324144.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.192146).

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>G	p.Ala624Gly	missense	Exon 5 of 5	NP_001311073.1	P51814-6
	ZNF41	NM_001324155.1		c.1997C>G	p.Ala666Gly	missense	Exon 4 of 4	NP_001311084.1	P51814-1
	ZNF41	NM_001324154.1		c.1973C>G	p.Ala658Gly	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>G	p.Ala624Gly	missense	Exon 5 of 5	ENSP00000508254.1	P51814-6
	ZNF41	ENST00000313116.11	TSL:1	c.1871C>G	p.Ala624Gly	missense	Exon 5 of 5	ENSP00000315173.7	P51814-6
	ZNF41	ENST00000377065.8	TSL:1	c.1871C>G	p.Ala624Gly	missense	Exon 5 of 5	ENSP00000366265.4	P51814-6

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111366 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098209 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363567

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 842122

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

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111366 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33616

African (AFR) AF: 0.00 AC: 0 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: 0.0000188 AC: 1 AN: 53059

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	20
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.053
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.35	T
Polyphen		0.97	D
Vest4		0.15
MVP		0.56
MPC		0.89
ClinPred		0.40	T
GERP RS		1.9
gMVP		0.052
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;