chr1-229305234-A-G

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

3
1
13

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]

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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 HGVSp Effect #exon/exons MANE UniProt
RAB4ANM_004578.4 linkuse as main transcriptc.*1441A>G 3_prime_UTR_variant 8/8 ENST00000366690.5
RAB4ANM_001271998.2 linkuse as main transcriptc.*1441A>G 3_prime_UTR_variant 6/6
RAB4ANR_073545.2 linkuse as main transcriptn.2289A>G non_coding_transcript_exon_variant 8/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RAB4AENST00000366690.5 linkuse as main transcriptc.*1441A>G 3_prime_UTR_variant 8/81 NM_004578.4 P1
RAB4AENST00000618010.4 linkuse as main transcriptc.*1441A>G 3_prime_UTR_variant 6/63

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000405
AC:
1
AN:
246954
Hom.:
0
AF XY:
0.00000749
AC XY:
1
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:
4
AN:
1456994
Hom.:
0
Cov.:
29
AF XY:
0.00000414
AC XY:
3
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.:
33
ExAC
AF:
0.00000824
AC:
1
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 submitterclinical testingAmbry GeneticsMay 12, 2024The 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
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
9.1
DANN
Uncertain
0.98
DEOGEN2
Benign
0.084
T
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.024
N
LIST_S2
Benign
0.33
T
M_CAP
Benign
0.0033
T
MetaRNN
Benign
0.070
T
MetaSVM
Benign
-0.99
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.35
T
PROVEAN
Pathogenic
-5.0
D
REVEL
Benign
0.097
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.046
B
Vest4
0.20
MutPred
0.14
Loss of helix (P = 0.0237);
MVP
0.14
MPC
0.13
ClinPred
0.22
T
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.

Other links and lift over

dbSNP: rs766686154; hg19: chr1-229440981; API