X-75421979-T-A

Variant names:

• chrX-75421979-T-A
• rs2083649735
• NM_144969.3:c.748A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144969.3(ZDHHC15):​c.748A>T​(p.Thr250Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZDHHC15 NM_144969.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

Genes affected

ZDHHC15 (HGNC:20342): (zinc finger DHHC-type palmitoyltransferase 15) The protein encoded by this gene belongs to the DHHC palmitoyltransferase family. Mutations in this gene are associated with mental retardatio X-linked type 91 (MRX91). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ZDHHC15 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 91

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

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069895566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC15	NM_144969.3	c.748A>T	p.Thr250Ser	missense_variant	Exon 9 of 12	ENST00000373367.8	NP_659406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC15	ENST00000373367.8	c.748A>T	p.Thr250Ser	missense_variant	Exon 9 of 12	1	NM_144969.3	ENSP00000362465.3
ZDHHC15	ENST00000541184.1	c.721A>T	p.Thr241Ser	missense_variant	Exon 8 of 11	2		ENSP00000445420.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748A>T (p.T250S) alteration is located in exon 9 (coding exon 9) of the ZDHHC15 gene. This alteration results from a A to T substitution at nucleotide position 748, causing the threonine (T) at amino acid position 250 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.075	T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.51	N;.
PhyloP100		2.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.27	N;N
REVEL	Benign	0.040
Sift	Benign	0.39	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0010	B;.
Vest4		0.17
MutPred		0.29		Gain of disorder (P = 0.0813);.;
MVP		0.068
MPC		0.34
ClinPred		0.59	D
GERP RS		4.0
Varity_R		0.098
gMVP		0.41
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2083649735; hg19: chrX-74641814;