8-17621105-A-G

Position:

• chr8-17621105-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001372073.1(PDGFRL):​c.408A>G​(p.Ala136Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,612,074 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (54 hom.)
• Consequence: PDGFRL NM_001372073.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -6.29

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-17621105-A-G is Benign according to our data. Variant chr8-17621105-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1048868.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-6.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00775 (11308/1459882) while in subpopulation MID AF= 0.0221 (127/5736). AF 95% confidence interval is 0.019. There are 54 homozygotes in gnomad4_exome. There are 5596 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRL	NM_001372073.1	c.408A>G	p.Ala136Ala	synonymous_variant	3/6	ENST00000251630.11	NP_001359002.1
PDGFRL	NM_006207.2	c.408A>G	p.Ala136Ala	synonymous_variant	4/7		NP_006198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRL	ENST00000251630.11	c.408A>G	p.Ala136Ala	synonymous_variant	3/6	5	NM_001372073.1	ENSP00000251630.4
PDGFRL	ENST00000541323.1	c.408A>G	p.Ala136Ala	synonymous_variant	4/7	2		ENSP00000444211.1
PDGFRL	ENST00000673645.1	c.*22A>G		downstream_gene_variant				ENSP00000501219.1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 926 AN: 152074 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00935

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00637 AC: 1596 AN: 250448 Hom.: 9 AF XY: 0.00668 AC XY: 904 AN XY: 135392

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.000708

Gnomad SAS exome AF: 0.00591

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00943

Gnomad OTH exome AF: 0.00721

GnomAD4 exome AF: 0.00775 AC: 11308 AN: 1459882 Hom.: 54 Cov.: 30 AF XY: 0.00771 AC XY: 5596 AN XY: 726188

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00630

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.00543

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00885

Gnomad4 OTH exome AF: 0.00735

GnomAD4 genome AF: 0.00610 AC: 929 AN: 152192 Hom.: 4 Cov.: 31 AF XY: 0.00563 AC XY: 419 AN XY: 74398

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000778

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00935

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00757 Hom.: 1

Bravo AF: 0.00612

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0112

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PDGFRL: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.075
DANN	Benign	0.23

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: rs34445293; hg19: chr8-17478614;