3-142684073-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001145319.2(PLS1):c.647C>T(p.Ser216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,613,500 control chromosomes in the GnomAD database, including 817 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.041 (426 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (391 hom.)
• Consequence: PLS1 NM_001145319.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.00

Genes affected

PLS1 (HGNC:9090): (plastin 1) Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. The protein encoded by this gene is a third distinct plastin isoform, which is specifically expressed at high levels in the small intestine. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. A pseudogene of this gene is found on chromosome 11.[provided by RefSeq, Feb 2010]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033848286).
• BP6: Variant 3-142684073-C-T is Benign according to our data. Variant chr3-142684073-C-T is described in ClinVar as [Benign]. Clinvar id is 1276295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLS1	NM_001145319.2	c.647C>T	p.Ser216Leu	missense_variant	7/16	ENST00000457734.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLS1	ENST00000457734.7	c.647C>T	p.Ser216Leu	missense_variant	7/16	2	NM_001145319.2	P1
	ENST00000690164.1	n.119-26867G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6293 AN: 151932 Hom.: 423 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0108 AC: 2717 AN: 251308 Hom.: 185 AF XY: 0.00783 AC XY: 1063 AN XY: 135816

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00430 AC: 6291 AN: 1461450 Hom.: 391 Cov.: 31 AF XY: 0.00365 AC XY: 2655 AN XY: 727072

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.00847

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.00904

GnomAD4 genome AF: 0.0415 AC: 6307 AN: 152050 Hom.: 426 Cov.: 32 AF XY: 0.0404 AC XY: 3002 AN XY: 74308

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.00714 Hom.: 92

Bravo AF: 0.0473

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.141 AC: 620

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0134 AC: 1626

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D;.;D;D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	L;.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.072
MPC		0.18
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.060
gMVP		0.30

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: rs35435507; hg19: chr3-142402915; COSMIC: COSV61834949;