14-69500943-A-G

Position:

• chr14-69500943-A-G

Variant summary

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

The NM_001161498.2(PLEKHD1):​c.406A>G​(p.Lys136Glu) 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLEKHD1 NM_001161498.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.37

Genes affected

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

PLEKHD1 (HGNC:):

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.406A>G	p.Lys136Glu	missense_variant	4/13	ENST00000322564.9	NP_001154970.1
PLEKHD1	XM_017021290.1	c.112A>G	p.Lys38Glu	missense_variant	4/13		XP_016876779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHD1	ENST00000322564.9	c.406A>G	p.Lys136Glu	missense_variant	4/13	1	NM_001161498.2	ENSP00000317175.7
PLEKHD1	ENST00000556123.1	n.1252A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1399166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690086

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 16, 2023

The c.406A>G (p.K136E) alteration is located in exon 4 (coding exon 4) of the PLEKHD1 gene. This alteration results from a A to G substitution at nucleotide position 406, causing the lysine (K) at amino acid position 136 to be replaced by a glutamic acid (E). 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	0.65
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.11	T
Vest4		0.76
MutPred		0.56		Loss of MoRF binding (P = 0.0024);
MVP		0.048
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.29
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs1013618922; hg19: chr14-69967660;