1-229305246-G-A

Position:

• chr1-229305246-G-A

Variant summary

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

The NM_004578.4(RAB4A):​c.*1453G>A variant causes a 3 prime UTR 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAB4A NM_004578.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.662

Genes affected

RAB4A (HGNC:9781): (RAB4A, member RAS oncogene family) This gene is a member of the largest group in the Ras superfamily of small GTPases, which regulate membrane trafficking. The encoded protein is associated with early endosomes and is involved in their sorting and recycling. The protein also plays a role in regulating the recycling of receptors from endosomes to the plasma membrane. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2012]

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=0.13701564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB4A	NM_004578.4	c.*1453G>A		3_prime_UTR_variant	8/8	ENST00000366690.5
RAB4A	NM_001271998.2	c.*1453G>A		3_prime_UTR_variant	6/6
RAB4A	NR_073545.2	n.2301G>A		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB4A	ENST00000366690.5	c.*1453G>A		3_prime_UTR_variant	8/8	1	NM_004578.4	P1
RAB4A	ENST00000618010.4	c.*1453G>A		3_prime_UTR_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Jun 29, 2023

The c.112G>A (p.E38K) alteration is located in exon 1 (coding exon 1) of the SPHAR gene. This alteration results from a G to A substitution at nucleotide position 112, causing the glutamic acid (E) at amino acid position 38 to be replaced by a lysine (K). 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
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.70	P
Vest4		0.29
MutPred		0.24		Gain of ubiquitination at E38 (P = 0.068);
MVP		0.13
MPC		0.13
ClinPred		0.68	D
GERP RS		1.9
Varity_R		0.50
gMVP		0.033

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: chr1-229440993;