chr20-56412474-A-T

Variant names:

• chr20-56412474-A-T
• rs138191448
• NM_020356.4:c.16A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020356.4(CASS4):​c.16A>T​(p.Ile6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I6V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASS4 NM_020356.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 2 publications found

Genes affected

CASS4 (HGNC:15878): (Cas scaffold protein family member 4) Enables protein tyrosine kinase binding activity. Involved in several processes, including positive regulation of protein kinase B signaling; positive regulation of protein tyrosine kinase activity; and positive regulation of substrate adhesion-dependent cell spreading. Located in focal adhesion. Part of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05571738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASS4	NM_020356.4	c.16A>T	p.Ile6Phe	missense_variant	Exon 1 of 6	ENST00000679887.1	NP_065089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASS4	ENST00000679887.1	c.16A>T	p.Ile6Phe	missense_variant	Exon 1 of 6		NM_020356.4	ENSP00000506506.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.0020
DANN	Benign	0.57
DEOGEN2	Benign	0.0094	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		-1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.032
Sift	Benign	0.039	D;T
Sift4G	Uncertain	0.049	D;T
Polyphen		0.077	B;B
Vest4		0.14
MutPred		0.31		Loss of catalytic residue at I6 (P = 0.1205);Loss of catalytic residue at I6 (P = 0.1205);
MVP		0.014
ClinPred		0.10	T
GERP RS		-11
PromoterAI		0.015	Neutral
Varity_R		0.065
gMVP		0.30
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs138191448; hg19: chr20-54987530;