chr8-17589618-T-C

Position:

• chr8-17589618-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001372073.1(PDGFRL):​c.206T>C​(p.Met69Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,614,018 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: PDGFRL NM_001372073.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.933

Genes affected

PDGFRL (HGNC:8805): (platelet derived growth factor receptor like) This gene encodes a protein with significant sequence similarity to the ligand binding domain of platelet-derived growth factor receptor beta. Mutations in this gene, or deletion of a chromosomal segment containing this gene, are associated with sporadic hepatocellular carcinomas, colorectal cancers, and non-small cell lung cancers. This suggests this gene product may function as a tumor suppressor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015561879).
• BP6: Variant 8-17589618-T-C is Benign according to our data. Variant chr8-17589618-T-C is described in ClinVar as [Benign]. Clinvar id is 714375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1657/152196) while in subpopulation AFR AF= 0.0382 (1585/41524). AF 95% confidence interval is 0.0366. There are 40 homozygotes in gnomad4. There are 733 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRL	NM_001372073.1	c.206T>C	p.Met69Thr	missense_variant	2/6	ENST00000251630.11	NP_001359002.1
PDGFRL	NM_006207.2	c.206T>C	p.Met69Thr	missense_variant	3/7		NP_006198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRL	ENST00000251630.11	c.206T>C	p.Met69Thr	missense_variant	2/6	5	NM_001372073.1	ENSP00000251630.4
PDGFRL	ENST00000541323.1	c.206T>C	p.Met69Thr	missense_variant	3/7	2		ENSP00000444211.1
PDGFRL	ENST00000673645.1	c.206T>C	p.Met69Thr	missense_variant	3/4			ENSP00000501219.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1654 AN: 152078 Hom.: 39 Cov.: 31

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00283 AC: 712 AN: 251442 Hom.: 11 AF XY: 0.00215 AC XY: 292 AN XY: 135892

Gnomad AFR exome AF: 0.0388

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00115 AC: 1686 AN: 1461822 Hom.: 35 Cov.: 32 AF XY: 0.00100 AC XY: 729 AN XY: 727216

Gnomad4 AFR exome AF: 0.0411

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000692

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.0109 AC: 1657 AN: 152196 Hom.: 40 Cov.: 31 AF XY: 0.00985 AC XY: 733 AN XY: 74418

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00233 Hom.: 7

Bravo AF: 0.0123

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0322 AC: 142

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.1
DANN	Benign	0.55
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.60	.;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.030	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.76	N;N
REVEL	Benign	0.038
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.18
MVP		0.072
MPC		0.0054
ClinPred		0.0014	T
GERP RS		1.9
Varity_R		0.062
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs35704589; hg19: chr8-17447127;