9-36058819-T-G

Position:

• chr9-36058819-T-G

Variant summary

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

The ENST00000377966.4(RECK):​c.160-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,578,842 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (7 hom., cov: 30)
  • Exomes 𝑓: 0.013 (136 hom.)
• Consequence: RECK ENST00000377966.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005283
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.127

Genes affected

RECK (HGNC:11345): (reversion inducing cysteine rich protein with kazal motifs) The protein encoded by this gene is a cysteine-rich, extracellular protein with protease inhibitor-like domains whose expression is suppressed strongly in many tumors and cells transformed by various kinds of oncogenes. In normal cells, this membrane-anchored glycoprotein may serve as a negative regulator for matrix metalloproteinase-9, a key enzyme involved in tumor invasion and metastasis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-36058819-T-G is Benign according to our data. Variant chr9-36058819-T-G is described in ClinVar as [Benign]. Clinvar id is 770385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.013 (18533/1428246) while in subpopulation NFE AF= 0.0155 (16943/1095510). AF 95% confidence interval is 0.0153. There are 136 homozygotes in gnomad4_exome. There are 9072 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECK	NM_021111.3	c.160-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000377966.4	NP_066934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECK	ENST00000377966.4	c.160-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021111.3	ENSP00000367202	P1
RECK	ENST00000479053.1	n.219-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
RECK	ENST00000475774.5	n.269-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1255 AN: 150480 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.00295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00489

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00335

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00531

GnomAD3 exomes AF: 0.00771 AC: 1763 AN: 228778 Hom.: 7 AF XY: 0.00801 AC XY: 998 AN XY: 124522

Gnomad AFR exome AF: 0.00218

Gnomad AMR exome AF: 0.00429

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00410

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.00666

GnomAD4 exome AF: 0.0130 AC: 18533 AN: 1428246 Hom.: 136 Cov.: 31 AF XY: 0.0128 AC XY: 9072 AN XY: 710704

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.00186

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.00458

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00834 AC: 1256 AN: 150596 Hom.: 7 Cov.: 30 AF XY: 0.00724 AC XY: 533 AN XY: 73592

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.00489

Gnomad4 ASJ AF: 0.00174

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00336

Gnomad4 FIN AF: 0.00387

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.00573

Alfa AF: 0.0133 Hom.: 4

Bravo AF: 0.00828

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	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0053
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.19		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: rs71521299; hg19: chr9-36058816;