chr14-67562157-C-T

Position:

• chr14-67562157-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020715.3(PLEKHH1):​c.526C>T​(p.Arg176Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,611,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PLEKHH1 NM_020715.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.791

Genes affected

PLEKHH1 (HGNC:17733): (pleckstrin homology, MyTH4 and FERM domain containing H1) Predicted to be located in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

GPHN (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05796516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHH1	NM_020715.3	c.526C>T	p.Arg176Trp	missense_variant	7/29	ENST00000329153.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHH1	ENST00000329153.10	c.526C>T	p.Arg176Trp	missense_variant	7/29	1	NM_020715.3	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000651 AC: 16 AN: 245590 Hom.: 0 AF XY: 0.0000600 AC XY: 8 AN XY: 133358

Gnomad AFR exome AF: 0.000737

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1458880 Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22 AN XY: 725382

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74358

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000254 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.020	D
Polyphen		0.66	P
Vest4		0.076
MVP		0.38
MPC		0.32
ClinPred		0.069	T
GERP RS		3.4
Varity_R		0.031
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs368366400; hg19: chr14-68028874; COSMIC: COSV61280826;