14-69524309-A-C

Position:

• chr14-69524309-A-C

Variant summary

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

The NM_001161498.2(PLEKHD1):​c.731A>C​(p.Gln244Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHD1 NM_001161498.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

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/exons	MANE	Protein	UniProt
PLEKHD1	NM_001161498.2	c.731A>C	p.Gln244Pro	missense_variant	8/13	ENST00000322564.9	NP_001154970.1
PLEKHD1	XM_017021290.1	c.437A>C	p.Gln146Pro	missense_variant	8/13		XP_016876779.1
PLEKHD1	XM_011536762.2	c.350A>C	p.Gln117Pro	missense_variant	5/10		XP_011535064.1
PLEKHD1	XM_011536763.2	c.182A>C	p.Gln61Pro	missense_variant	3/8		XP_011535065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHD1	ENST00000322564.9	c.731A>C	p.Gln244Pro	missense_variant	8/13	1	NM_001161498.2	ENSP00000317175.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Apr 06, 2024

The c.731A>C (p.Q244P) alteration is located in exon 8 (coding exon 8) of the PLEKHD1 gene. This alteration results from a A to C substitution at nucleotide position 731, causing the glutamine (Q) at amino acid position 244 to be replaced by a proline (P). 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	0.91
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.026	D
Vest4		0.79
MutPred		0.18		Gain of phosphorylation at T246 (P = 0.1131);
MVP		0.067
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-69991026;