14-69525957-A-T

Variant names:

• chr14-69525957-A-T
• NM_001161498.2:c.758A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001161498.2(PLEKHD1):​c.758A>T​(p.Glu253Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLEKHD1 NM_001161498.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.25

Genes affected

PLEKHD1 (HGNC:20148): (pleckstrin homology and coiled-coil domain containing D1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHD1	NM_001161498.2	c.758A>T	p.Glu253Val	missense_variant	Exon 9 of 13	ENST00000322564.9	NP_001154970.1
PLEKHD1	XM_017021290.1	c.464A>T	p.Glu155Val	missense_variant	Exon 9 of 13		XP_016876779.1
PLEKHD1	XM_011536762.2	c.377A>T	p.Glu126Val	missense_variant	Exon 6 of 10		XP_011535064.1
PLEKHD1	XM_011536763.2	c.209A>T	p.Glu70Val	missense_variant	Exon 4 of 8		XP_011535065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHD1	ENST00000322564.9	c.758A>T	p.Glu253Val	missense_variant	Exon 9 of 13	1	NM_001161498.2	ENSP00000317175.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398866 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758A>T (p.E253V) alteration is located in exon 9 (coding exon 9) of the PLEKHD1 gene. This alteration results from a A to T substitution at nucleotide position 758, causing the glutamic acid (E) at amino acid position 253 to be replaced by a valine (V). 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Vest4		0.90
MutPred		0.11		Gain of methylation at K254 (P = 0.0371);
MVP		0.072
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.51
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-69992674;