9-124971453-A-G

Position:

• chr9-124971453-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001144877.3(SCAI):​c.1591T>C​(p.Phe531Leu) 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: SCAI NM_001144877.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

Genes affected

SCAI (HGNC:26709): (suppressor of cancer cell invasion) This gene encodes a regulator of cell migration. The encoded protein appears to function in the RhoA (ras homolog gene family, member A)-Dia1 (diaphanous homolog 1) signal transduction pathway. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCAI	NM_001144877.3	c.1591T>C	p.Phe531Leu	missense_variant	17/18	ENST00000336505.11	NP_001138349.1
SCAI	NM_173690.5	c.1660T>C	p.Phe554Leu	missense_variant	18/19		NP_775961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCAI	ENST00000336505.11	c.1591T>C	p.Phe531Leu	missense_variant	17/18	1	NM_001144877.3	ENSP00000336756.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Oct 18, 2021

The c.1660T>C (p.F554L) alteration is located in exon 18 (coding exon 18) of the SCAI gene. This alteration results from a T to C substitution at nucleotide position 1660, causing the phenylalanine (F) at amino acid position 554 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.96	D;P
Vest4		0.83
MutPred		0.46		Loss of catalytic residue at F531 (P = 0.3407);.;
MVP		0.53
MPC		1.9
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.53
gMVP		0.69

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: rs1016280095; hg19: chr9-127733732;