rs16932912

Positions:

• chr9-36087879-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021111.3(RECK):​c.823G>A​(p.Val275Ile) variant causes a missense change. The variant allele was found at a frequency of 0.076 in 1,613,484 control chromosomes in the GnomAD database, including 5,711 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.087 (702 hom., cov: 32)
  • Exomes 𝑓: 0.075 (5009 hom.)
• Consequence: RECK NM_021111.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016192198).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECK	NM_021111.3	c.823G>A	p.Val275Ile	missense_variant	9/21	ENST00000377966.4	NP_066934.1
RECK	NM_001316345.2	c.439G>A	p.Val147Ile	missense_variant	11/23		NP_001303274.1
RECK	XM_017015207.2	c.712G>A	p.Val238Ile	missense_variant	10/22		XP_016870696.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECK	ENST00000377966.4	c.823G>A	p.Val275Ile	missense_variant	9/21	1	NM_021111.3	ENSP00000367202.3

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13184 AN: 152060 Hom.: 703 Cov.: 32

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.0830

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0865

GnomAD3 exomes AF: 0.0921 AC: 23131 AN: 251154 Hom.: 1542 AF XY: 0.0882 AC XY: 11969 AN XY: 135732

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.0949

Gnomad ASJ exome AF: 0.0751

Gnomad EAS exome AF: 0.306

Gnomad SAS exome AF: 0.0676

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0793

GnomAD4 exome AF: 0.0749 AC: 109467 AN: 1461306 Hom.: 5009 Cov.: 32 AF XY: 0.0740 AC XY: 53781 AN XY: 726984

Gnomad4 AFR exome AF: 0.0935

Gnomad4 AMR exome AF: 0.0936

Gnomad4 ASJ exome AF: 0.0737

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.0672

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.0662

Gnomad4 OTH exome AF: 0.0770

GnomAD4 genome AF: 0.0867 AC: 13199 AN: 152178 Hom.: 702 Cov.: 32 AF XY: 0.0891 AC XY: 6631 AN XY: 74398

Gnomad4 AFR AF: 0.0925

Gnomad4 AMR AF: 0.0870

Gnomad4 ASJ AF: 0.0695

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.0824

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0641

Gnomad4 OTH AF: 0.0851

Alfa AF: 0.0726 Hom.: 1182

Bravo AF: 0.0886

TwinsUK AF: 0.0739 AC: 274

ALSPAC AF: 0.0682 AC: 263

ESP6500AA AF: 0.0917 AC: 404

ESP6500EA AF: 0.0665 AC: 572

ExAC AF: 0.0888 AC: 10775

Asia WGS AF: 0.149 AC: 516 AN: 3478

EpiCase AF: 0.0596

EpiControl AF: 0.0599

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.13
Sift	Benign	0.33	T
Sift4G	Benign	0.42	T
Polyphen		0.67	P
Vest4		0.10
MPC		0.27
ClinPred		0.0079	T
GERP RS		5.5
Varity_R		0.055
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16932912; hg19: chr9-36087876; COSMIC: COSV65035455; COSMIC: COSV65035455;