19-41956872-C-T

Variant names:

• chr19-41956872-C-T
• rs1236009980
• NM_006423.3:c.532G>A

Variant summary

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

The NM_006423.3(RABAC1):​c.532G>A​(p.Glu178Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RABAC1 NM_006423.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.98

Genes affected

RABAC1 (HGNC:9794): (Rab acceptor 1) Enables identical protein binding activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABAC1	NM_006423.3	c.532G>A	p.Glu178Lys	missense_variant	Exon 5 of 5	ENST00000222008.11	NP_006414.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABAC1	ENST00000222008.11	c.532G>A	p.Glu178Lys	missense_variant	Exon 5 of 5	1	NM_006423.3	ENSP00000222008.5
ENSG00000285505	ENST00000644613.1	n.*354G>A		downstream_gene_variant				ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460046 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726182

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.532G>A (p.E178K) alteration is located in exon 5 (coding exon 5) of the RABAC1 gene. This alteration results from a G to A substitution at nucleotide position 532, causing the glutamic acid (E) at amino acid position 178 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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.6	.;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	.;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.016	.;D;.
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.58
MutPred		0.76		.;Gain of ubiquitination at E178 (P = 0.0094);.;
MVP		0.64
MPC		1.1
ClinPred		0.96	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1236009980; hg19: chr19-42461024;