Genetic Variant ZNF41:c.73-42A>C (chrX-47456440-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_ModerateBP6_ModerateBS2

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:1B:2

Conservation

PhyloP100: -0.497

Publications

0 publications found

Variant links:

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

ZNF41 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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

Gene	Transcript	Tags	HGVSc	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.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000381

AC XY:

138

AN XY:

362016

show subpopulations

African (AFR)

AF:

0.00303

AC:

AN:

26378

American (AMR)

AF:

0.000796

AC:

AN:

35158

Ashkenazi Jewish (ASJ)

AF:

0.00646

AC:

125

AN:

19339

East Asian (EAS)

AF:

0.00

AC:

AN:

30128

South Asian (SAS)

AF:

0.00

AC:

AN:

54098

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40399

Middle Eastern (MID)

AF:

0.00194

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.000210

AC:

177

AN:

840992

Other (OTH)

AF:

0.00122

AC:

AN:

46009

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00112

AC:

125

AN:

112048

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

34224

show subpopulations

African (AFR)

AF:

0.00273

AC:

AN:

30825

American (AMR)

AF:

0.000856

AC:

AN:

10515

Ashkenazi Jewish (ASJ)

AF:

0.00793

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00

AC:

AN:

2698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000131

AC:

AN:

53240

Other (OTH)

AF:

0.00265

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000658

Hom.:

Bravo

AF:

0.00129

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000601

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

ZNF41-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.67

FATHMM_MKL

Benign

0.032

PhyloP100

-0.50

GERP RS

-1.6

Mutation Taster

=41/59

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over