Variant 1-229305234-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004578.4(RAB4A):c.*1441A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RAB4A
NM_004578.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0180

Variant links:

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]

RAB4A links:

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ACMG classification

Classification made for transcript

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=0.07044685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
RAB4A	NM_004578.4 linkuse as main transcript	c.*1441A>G	3_prime_UTR_variant	8/8	ENST00000366690.5
RAB4A	NM_001271998.2 linkuse as main transcript	c.*1441A>G	3_prime_UTR_variant	6/6
RAB4A	NR_073545.2 linkuse as main transcript	n.2289A>G	non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB4A	ENST00000366690.5 linkuse as main transcript	c.*1441A>G		3_prime_UTR_variant	8/8	1	NM_004578.4	P1
RAB4A	ENST00000618010.4 linkuse as main transcript	c.*1441A>G		3_prime_UTR_variant	6/6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246954

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133502

show subpopulations

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1456994

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724640

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2024

The c.100A>G (p.N34D) alteration is located in exon 1 (coding exon 1) of the SPHAR gene. This alteration results from a A to G substitution at nucleotide position 100, causing the asparagine (N) at amino acid position 34 to be replaced by an aspartic acid (D). 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

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.1

DANN

Uncertain

0.98

DEOGEN2

Benign

0.084

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.33

M_CAP

Benign

0.0033

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.097

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.046

Vest4

0.20

MutPred

0.14

Loss of helix (P = 0.0237);

MVP

0.14

MPC

0.13

ClinPred

0.22

GERP RS

-2.2

Varity_R

0.49

gMVP

0.0069

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over