Genetic Variant NM_032968.5:c.1657A>G (chrX-91877897-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032968.5(PCDH11X):c.1657A>G(p.Asn553Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N553T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 20)

Consequence

PCDH11X
NM_032968.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.24

Publications

0 publications found

Variant links:

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]

PCDH11X links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032968.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH11X	NM_032968.5	MANE Select	c.1657A>G	p.Asn553Asp	missense	Exon 6 of 11	NP_116750.1	Q9BZA7-1
PCDH11X	NM_001168360.1		c.1657A>G	p.Asn553Asp	missense	Exon 2 of 6	NP_001161832.1	Q9BZA7-8
PCDH11X	NM_032969.4		c.1657A>G	p.Asn553Asp	missense	Exon 2 of 6	NP_116751.1	Q9BZA7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH11X	ENST00000682573.1	MANE Select	c.1657A>G	p.Asn553Asp	missense	Exon 6 of 11	ENSP00000507225.1	Q9BZA7-1
PCDH11X	ENST00000373094.5	TSL:1	c.1657A>G	p.Asn553Asp	missense	Exon 2 of 7	ENSP00000362186.1	Q9BZA7-1
PCDH11X	ENST00000406881.3	TSL:1	c.1657A>G	p.Asn553Asp	missense	Exon 2 of 6	ENSP00000384758.1	Q9BZA7-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.65

PhyloP100

7.2

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

REVEL

Benign

0.29

Sift

Benign

0.041

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.61

MutPred

0.52

Gain of phosphorylation at T551 (P = 0.0907)

MVP

0.76

MPC

2.4

ClinPred

0.90

GERP RS

5.4

Varity_R

0.50

gMVP

0.45

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over