rs201140907

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-47456440-T-G
• chrX-47456440-T-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_Moderate BP6_Moderate BS2

The NM_001324155.1(ZNF41):​c.159-2A>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,208,674 control chromosomes in the GnomAD database, including 1 homozygotes. There are 172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 34 hem., cov: 23)
  • Exomes 𝑓: 0.00043 (1 hom. 138 hem.)
• Consequence: ZNF41 NM_001324155.1 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00006790
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:2
• 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: Likely_benign. 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.
• BP6: Variant X-47456440-T-G is Benign according to our data. Variant chrX-47456440-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 9761.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 34 XL gene

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>C		intron	N/A	NP_001311073.1	P51814-6
	ZNF41	NM_001324155.1		c.159-2A>C		splice_acceptor intron	N/A	NP_001311084.1	P51814-1
	ZNF41	NM_001324154.1		c.159-26A>C		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>C		intron	N/A	ENSP00000508254.1	P51814-6
	ZNF41	ENST00000313116.11	TSL:1	c.73-42A>C		intron	N/A	ENSP00000315173.7	P51814-6
	ZNF41	ENST00000377065.8	TSL:1	c.73-42A>C		intron	N/A	ENSP00000366265.4	P51814-6

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 125 AN: 112048 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000856

Gnomad ASJ AF: 0.00793

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000131

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.000646 AC: 118 AN: 182638 AF XY: 0.000536

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00643

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000433 AC: 475 AN: 1096626 Hom.: 1 Cov.: 31 AF XY: 0.000381 AC XY: 138 AN XY: 362016

African (AFR) AF: 0.00303 AC: 80 AN: 26378

American (AMR) AF: 0.000796 AC: 28 AN: 35158

Ashkenazi Jewish (ASJ) AF: 0.00646 AC: 125 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: 0.0000248 AC: 1 AN: 40399

Middle Eastern (MID) AF: 0.00194 AC: 8 AN: 4125

European-Non Finnish (NFE) AF: 0.000210 AC: 177 AN: 840992

Other (OTH) AF: 0.00122 AC: 56 AN: 46009

GnomAD4 genome AF: 0.00112 AC: 125 AN: 112048 Hom.: 0 Cov.: 23 AF XY: 0.000993 AC XY: 34 AN XY: 34224

African (AFR) AF: 0.00273 AC: 84 AN: 30825

American (AMR) AF: 0.000856 AC: 9 AN: 10515

Ashkenazi Jewish (ASJ) AF: 0.00793 AC: 21 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000131 AC: 7 AN: 53240

Other (OTH) AF: 0.00265 AC: 4 AN: 1508

Alfa AF: 0.000658 Hom.: 14

Bravo AF: 0.00129

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000601 AC: 73

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	ZNF41-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.67
FATHMM_MKL	Benign	0.032	N
PhyloP100		-0.50
GERP RS		-1.6
Mutation Taster		=41/59	polymorphism (auto)

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;