X-85246027-C-T

Variant names:

• chrX-85246027-C-T
• rs41311563
• NM_001330574.2:c.-286+5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330574.2(ZNF711):​c.-286+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 111,010 control chromosomes in the GnomAD database, including 2,464 homozygotes. There are 6,801 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (2464 hom., 6801 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: ZNF711 NM_001330574.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001267
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.716
• Publications: 1 publications found

Genes affected

ZNF711 (HGNC:13128): (zinc finger protein 711) This gene encodes a zinc finger protein of unknown function. It bears similarity to a zinc finger protein which acts as a transcriptional activator. This gene lies in a region of the X chromosome which has been associated with cognitive disability. [provided by RefSeq, Jul 2008]

ZNF711 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 97

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-85246027-C-T is Benign according to our data. Variant chrX-85246027-C-T is described in ClinVar as [Benign]. Clinvar id is 130847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF711	NM_001330574.2	c.-286+5C>T		splice_region_variant, intron_variant	Intron 2 of 10	ENST00000674551.1	NP_001317503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF711	ENST00000674551.1	c.-286+5C>T		splice_region_variant, intron_variant	Intron 2 of 10		NM_001330574.2	ENSP00000502839.1
ZNF711	ENST00000360700.4	c.-644+5C>T		splice_region_variant, intron_variant	Intron 2 of 9	1		ENSP00000353922.4
ZNF711	ENST00000276123.7	c.-281+5C>T		splice_region_variant, intron_variant	Intron 2 of 9	1		ENSP00000276123.3
ZNF711	ENST00000373165.7	c.-27+5C>T		splice_region_variant, intron_variant	Intron 2 of 8	1		ENSP00000362260.3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 23959 AN: 110958 Hom.: 2466 Cov.: 23

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.0426

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.185

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.216 AC: 24003 AN: 111010 Hom.: 2464 Cov.: 23 AF XY: 0.204 AC XY: 6801 AN XY: 33288

African (AFR) AF: 0.403 AC: 12260 AN: 30437

American (AMR) AF: 0.154 AC: 1623 AN: 10539

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 476 AN: 2641

East Asian (EAS) AF: 0.152 AC: 535 AN: 3528

South Asian (SAS) AF: 0.199 AC: 532 AN: 2667

European-Finnish (FIN) AF: 0.161 AC: 947 AN: 5886

Middle Eastern (MID) AF: 0.134 AC: 29 AN: 216

European-Non Finnish (NFE) AF: 0.138 AC: 7293 AN: 52909

Other (OTH) AF: 0.185 AC: 279 AN: 1507

Alfa AF: 0.190 Hom.: 1100

Bravo AF: 0.219

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Intellectual disability, X-linked 97 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.3
DANN	Benign	0.49
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0020
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: rs41311563; hg19: chrX-84501033;