X-47456440-T-C

Variant names:

• chrX-47456440-T-C
• rs201140907
• NM_001324144.2:c.73-42A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001324155.1(ZNF41):​c.159-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,626 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZNF41 NM_001324155.1 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00006790
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.497
• Publications: 0 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 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06772101 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.9, offset of 24, new splice context is: gaccatgctgccttgaacAGcat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324155.1. 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.73-42A>G		intron	N/A	NP_001311073.1	P51814-6
	ZNF41	NM_001324155.1		c.159-2A>G		splice_acceptor intron	N/A	NP_001311084.1	P51814-1
	ZNF41	NM_001324154.1		c.159-26A>G		intron	N/A	NP_001311083.1	P51814-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF41	ENST00000684689.1	MANE Select	c.73-42A>G		intron	N/A	ENSP00000508254.1	P51814-6
	ZNF41	ENST00000313116.11	TSL:1	c.73-42A>G		intron	N/A	ENSP00000315173.7	P51814-6
	ZNF41	ENST00000377065.8	TSL:1	c.73-42A>G		intron	N/A	ENSP00000366265.4	P51814-6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096626 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362016

⚠️ 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: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.00 AC: 0 AN: 30128

South Asian (SAS) AF: 0.00 AC: 0 AN: 54098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40399

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840992

Other (OTH) AF: 0.00 AC: 0 AN: 46009

⚠️ 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.: 23

Alfa AF: 0.00 Hom.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.68
FATHMM_MKL	Benign	0.072	N
PhyloP100		-0.50
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201140907; hg19: chrX-47315839;