chr9-36100479-G-A

Position:

• chr9-36100479-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021111.3(RECK):​c.1234G>A​(p.Ala412Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RECK NM_021111.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.05

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECK	NM_021111.3	c.1234G>A	p.Ala412Thr	missense_variant	11/21	ENST00000377966.4
RECK	NM_001316345.2	c.850G>A	p.Ala284Thr	missense_variant	13/23
RECK	XM_017015207.2	c.1123G>A	p.Ala375Thr	missense_variant	12/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECK	ENST00000377966.4	c.1234G>A	p.Ala412Thr	missense_variant	11/21	1	NM_021111.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1234G>A (p.A412T) alteration is located in exon 11 (coding exon 11) of the RECK gene. This alteration results from a G to A substitution at nucleotide position 1234, causing the alanine (A) at amino acid position 412 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.32
Sift	Benign	0.32	T
Sift4G	Benign	0.35	T
Polyphen		0.91	P
Vest4		0.72
MutPred		0.78		Loss of catalytic residue at A412 (P = 0.1181);
MVP		0.70
MPC		0.40
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.26
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-36100476;