X-91835516-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_032968.5(PCDH11X):c.12G>T(p.Leu4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,209,089 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 150 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 7 hem., cov: 21)
  • Exomes 𝑓: 0.00037 (0 hom. 143 hem.)
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

PCDH11X (HGNC:8656): (protocadherin 11 X-linked) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 7 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene is located in a major X/Y block of homology and its Y homolog, despite divergence leading to coding region changes, is the most closely related cadherin family member. The protein is thought to play a fundamental role in cell-cell recognition essential for the segmental development and function of the central nervous system. Disruption of this gene may be associated with developmental dyslexia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03861949).
• BS2: High Hemizygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH11X	NM_032968.5	c.12G>T	p.Leu4Phe	missense_variant	5/11	ENST00000682573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH11X	ENST00000682573.1	c.12G>T	p.Leu4Phe	missense_variant	5/11		NM_032968.5	P4

Frequencies

GnomAD3 genomes AF: 0.000280 AC: 31 AN: 110884 Hom.: 0 Cov.: 21 AF XY: 0.000212 AC XY: 7 AN XY: 33080

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00147

Gnomad AMR AF: 0.0000973

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000240 AC: 44 AN: 183471 Hom.: 0 AF XY: 0.000309 AC XY: 21 AN XY: 67921

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000488

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000365 AC: 401 AN: 1098205 Hom.: 0 Cov.: 31 AF XY: 0.000393 AC XY: 143 AN XY: 363585

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.000462

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.000280 AC: 31 AN: 110884 Hom.: 0 Cov.: 21 AF XY: 0.000212 AC XY: 7 AN XY: 33080

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.0000973

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000602 Hom.: 3

Bravo AF: 0.000264

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.12G>T (p.L4F) alteration is located in exon 1 (coding exon 1) of the PCDH11X gene. This alteration results from a G to T substitution at nucleotide position 12, causing the leucine (L) at amino acid position 4 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	15
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.039	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.65	N;N;N;N;N;N
MutationTaster	Benign	0.94	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.041	D;D;D;T;D;D
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.0070	B;B;B;B;B;B
Vest4		0.067
MutPred		0.48		Gain of glycosylation at S5 (P = 0.135);Gain of glycosylation at S5 (P = 0.135);Gain of glycosylation at S5 (P = 0.135);Gain of glycosylation at S5 (P = 0.135);Gain of glycosylation at S5 (P = 0.135);Gain of glycosylation at S5 (P = 0.135);
MVP		0.54
MPC		1.3
ClinPred		0.011	T
GERP RS		1.4
Varity_R		0.19
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs144734965; hg19: chrX-91090515; COSMIC: COSV53503929;