X-85255298-A-G

Variant names:

• chrX-85255298-A-G
• NM_001330574.2:c.119A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001330574.2(ZNF711):​c.119A>G​(p.His40Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,998 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: ZNF711 NM_001330574.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.58
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41483867).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF711	NM_001330574.2	c.119A>G	p.His40Arg	missense_variant	Exon 5 of 11	ENST00000674551.1	NP_001317503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF711	ENST00000674551.1	c.119A>G	p.His40Arg	missense_variant	Exon 5 of 11		NM_001330574.2	ENSP00000502839.1
ZNF711	ENST00000360700.4	c.119A>G	p.His40Arg	missense_variant	Exon 4 of 10	1		ENSP00000353922.4
ZNF711	ENST00000276123.7	c.119A>G	p.His40Arg	missense_variant	Exon 5 of 10	1		ENSP00000276123.3
ZNF711	ENST00000373165.7	c.119A>G	p.His40Arg	missense_variant	Exon 4 of 9	1		ENSP00000362260.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097998 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 2 AN XY: 363358

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841919

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ZNF711 c.119A>G (p.His40Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182603 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.119A>G in individuals affected with X-Linked Intellectual Disability 97 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M;M
PhyloP100		8.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.61
MutPred		0.36		Loss of glycosylation at S44 (P = 0.1129);Loss of glycosylation at S44 (P = 0.1129);Loss of glycosylation at S44 (P = 0.1129);
MVP		0.31
MPC		0.78
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.38
gMVP		0.92
Mutation Taster		=67/33	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

hg19: chrX-84510304;