10-113767436-A-C

Variant names:

• chr10-113767436-A-C
• rs373783132
• NM_001395068.1:c.316A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001395068.1(PLEKHS1):​c.316A>C​(p.Ile106Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I106V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PLEKHS1 NM_001395068.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

Genes affected

PLEKHS1 (HGNC:26285): (pleckstrin homology domain containing S1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31187683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHS1	NM_001395068.1	c.316A>C	p.Ile106Leu	missense_variant	Exon 5 of 13	ENST00000694986.1	NP_001381997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHS1	ENST00000694986.1	c.316A>C	p.Ile106Leu	missense_variant	Exon 5 of 13		NM_001395068.1	ENSP00000511629.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.298A>C (p.I100L) alteration is located in exon 4 (coding exon 4) of the PLEKHS1 gene. This alteration results from a A to C substitution at nucleotide position 298, causing the isoleucine (I) at amino acid position 100 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.67	.;.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.83	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N;N;.;N
REVEL	Benign	0.25
Sift	Benign	0.072	T;D;.;T
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.47
MutPred		0.60		.;.;.;Loss of sheet (P = 0.1158);
MVP		0.24
MPC		0.24
ClinPred		0.53	D
GERP RS		3.4
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs373783132; hg19: chr10-115527195;