1-206584670-A-G

Variant names:

• chr1-206584670-A-G
• rs1553407191
• NM_182663.4:c.974A>G

Variant summary

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

The NM_182663.4(RASSF5):​c.974A>G​(p.His325Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RASSF5 NM_182663.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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]

EIF2D (HGNC:6583): (eukaryotic translation initiation factor 2D) This gene encodes a translation initiation factor involved in the recruitment and delivery of aminoacyl-tRNAs to the P-site of the eukaryotic ribosome in a GTP-independent manner. This gene was previously referred to as ligatin, but is now known to localize to the cytoplasm and localize and function with translation factors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

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=0.12434453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASSF5	NM_182663.4	c.974A>G	p.His325Arg	missense_variant	Exon 4 of 6	ENST00000579436.7	NP_872604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASSF5	ENST00000579436.7	c.974A>G	p.His325Arg	missense_variant	Exon 4 of 6	1	NM_182663.4	ENSP00000462099.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250696 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.974A>G (p.H325R) alteration is located in exon 4 (coding exon 4) of the RASSF5 gene. This alteration results from a A to G substitution at nucleotide position 974, causing the histidine (H) at amino acid position 325 to be replaced by an arginine (R). 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	0.080
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.055	T;.;.;.;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.88	L;L;.;.;.;.
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	0.27	T;T;T;.;T;T
Polyphen		0.0	B;B;.;.;B;.
Vest4		0.11
MutPred		0.53		Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);.;.;.;
MVP		0.35
ClinPred		0.24	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.63

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: rs1553407191; hg19: chr1-206758002;