NM_001897.5:c.914C>T

Variant names:

• chr15-75690151-G-A
• rs76827801
• NM_001897.5:c.914C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001897.5(CSPG4):​c.914C>T​(p.Thr305Met) variant causes a missense change. The variant allele was found at a frequency of 0.00903 in 142,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSPG4 NM_001897.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.15

Genes affected

CSPG4 (HGNC:2466): (chondroitin sulfate proteoglycan 4) A human melanoma-associated chondroitin sulfate proteoglycan plays a role in stabilizing cell-substratum interactions during early events of melanoma cell spreading on endothelial basement membranes. CSPG4 represents an integral membrane chondroitin sulfate proteoglycan expressed by human malignant melanoma cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Variant has high frequency in the AFR(0.0608651) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).
• BP4: Computational evidence support a benign effect (MetaRNN=0.003302157).
• BP6: Variant 15-75690151-G-A is Benign according to our data. Variant chr15-75690151-G-A is described in ClinVar as [Benign]. Clinvar id is 402567.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 = 0.00903 (1290/142802) while in subpopulation AFR AF= 0.0313 (1065/34032). AF 95% confidence interval is 0.0297. There are 0 homozygotes in gnomad4. There are 637 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPG4	NM_001897.5	c.914C>T	p.Thr305Met	missense_variant	Exon 3 of 10	ENST00000308508.5	NP_001888.2
CSPG4	XM_047432196.1	c.-149C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 10		XP_047288152.1
CSPG4	XM_047432196.1	c.-149C>T		5_prime_UTR_variant	Exon 3 of 10		XP_047288152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSPG4	ENST00000308508.5	c.914C>T	p.Thr305Met	missense_variant	Exon 3 of 10	1	NM_001897.5	ENSP00000312506.5

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1284 AN: 142732 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00293

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000663

Gnomad MID AF: 0.00685

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00914

GnomAD3 exomes AF: 0.00786 AC: 1926 AN: 244940 Hom.: 0 AF XY: 0.00666 AC XY: 887 AN XY: 133140

Gnomad AFR exome AF: 0.0727

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.00394

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00187

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00526

Gnomad OTH exome AF: 0.00502

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00477 AC: 6847 AN: 1435236 Hom.: 0 Cov.: 34 AF XY: 0.00465 AC XY: 3320 AN XY: 714496

Gnomad4 AFR exome AF: 0.0634

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.000462

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00145

Gnomad4 NFE exome AF: 0.00393

Gnomad4 OTH exome AF: 0.00549

GnomAD4 genome AF: 0.00903 AC: 1290 AN: 142802 Hom.: 0 Cov.: 33 AF XY: 0.00911 AC XY: 637 AN XY: 69902

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00293

Gnomad4 EAS AF: 0.000777

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000663

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00904

Alfa AF: 0.0138 Hom.: 0

ExAC AF: 0.0206 AC: 2502

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0033	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.031	D
Polyphen		0.99	D
Vest4		0.24
MPC		0.91
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.079
gMVP		0.62

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: rs76827801; hg19: chr15-75982492; COSMIC: COSV57889988;