X-102937978-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001031834.1(RAB40AL):c.660C>G(p.Ser220Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,210,394 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 122 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00035 (0 hom. 114 hem.)
• Consequence: RAB40AL NM_001031834.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0510

Genes affected

RAB40AL (HGNC:25410): (RAB40A like) This gene encodes a member of the Rab40 subfamily of Rab small GTP-binding proteins that contains a C-terminal suppressors of cytokine signaling box. Disruptions in this gene are associated with Duchenne muscular dystrophy. [provided by RefSeq, Apr 2010]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23990163).
• BP6: Variant X-102937978-C-G is Benign according to our data. Variant chrX-102937978-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440229.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chrX-102937978-C-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB40AL	NM_001031834.1	c.660C>G	p.Ser220Arg	missense_variant	1/1	ENST00000218249.7
LINC00630	NR_146589.1	n.1910-20670C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB40AL	ENST00000218249.7	c.660C>G	p.Ser220Arg	missense_variant	1/1		NM_001031834.1	P1
	ENST00000413528.1	n.420G>C		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.000267 AC: 30 AN: 112156 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34302

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000376

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000451

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000251 AC: 46 AN: 183520 Hom.: 0 AF XY: 0.000191 AC XY: 13 AN XY: 67948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000583

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: 0.000329

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000349 AC: 383 AN: 1098238 Hom.: 0 Cov.: 32 AF XY: 0.000314 AC XY: 114 AN XY: 363596

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000625

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: 0.000416

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000267 AC: 30 AN: 112156 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34302

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.000376

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000451

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000109

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 2023	The c.660C>G (p.S220R) alteration is located in exon 1 (coding exon 1) of the RAB40AL gene. This alteration results from a C to G substitution at nucleotide position 660, causing the serine (S) at amino acid position 220 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Uncertain	0.97
DEOGEN2	Benign	0.037	T
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.072
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.014	D
Polyphen		0.016	B
Vest4		0.62
MutPred		0.60		Gain of sheet (P = 0.0149);
MVP		0.82
MPC		0.54
ClinPred		0.053	T
GERP RS		-0.15
Varity_R		0.47
gMVP		0.090

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: rs148863690; hg19: chrX-102192906;