1-206507769-C-A

Position:

• chr1-206507769-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000579436.7(RASSF5):​c.167C>A​(p.Ala56Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,252,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: RASSF5 ENST00000579436.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

RASSF5 (HGNC:17609): (Ras association domain family member 5) This gene is a member of the Ras association domain family. It functions as a tumor suppressor, and is inactivated in a variety of cancers. The encoded protein localizes to centrosomes and microtubules, and associates with the GTP-activated forms of Ras, Rap1, and several other Ras-like small GTPases. The protein regulates lymphocyte adhesion and suppresses cell growth in response to activated Rap1 or Ras. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17732114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASSF5	NM_182663.4	c.167C>A	p.Ala56Glu	missense_variant	1/6	ENST00000579436.7	NP_872604.1
RASSF5	NM_182664.4	c.167C>A	p.Ala56Glu	missense_variant	1/5		NP_872605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASSF5	ENST00000579436.7	c.167C>A	p.Ala56Glu	missense_variant	1/6	1	NM_182663.4	ENSP00000462099.1
RASSF5	ENST00000581503.6	c.167C>A	p.Ala56Glu	missense_variant	1/4	1		ENSP00000464039.2
RASSF5	ENST00000580449.5	c.167C>A	p.Ala56Glu	missense_variant	1/5	1		ENSP00000462544.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000160 AC: 2 AN: 1252876 Hom.: 0 Cov.: 35 AF XY: 0.00000163 AC XY: 1 AN XY: 615068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.79e-7

Gnomad4 OTH exome AF: 0.0000194

GnomAD4 genome Cov.: 33

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

May 24, 2024

The c.167C>A (p.A56E) alteration is located in exon 1 (coding exon 1) of the RASSF5 gene. This alteration results from a C to A substitution at nucleotide position 167, causing the alanine (A) at amino acid position 56 to be replaced by a glutamic acid (E). 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	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.053	T;D;D
Polyphen		0.099	B;B;.
Vest4		0.21
MutPred		0.14		Loss of MoRF binding (P = 0.0443);Loss of MoRF binding (P = 0.0443);Loss of MoRF binding (P = 0.0443);
MVP		0.25
ClinPred		0.46	T
GERP RS		1.8
Varity_R		0.039
gMVP		0.45

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: chr1-206681102;