NM_080879.3:c.647G>T

Variant names:

• chrX-103500110-C-A
• rs200647197
• NM_080879.3:c.647G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_080879.3(RAB40A):​c.647G>T​(p.Ser216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,209,585 control chromosomes in the GnomAD database, including 1 homozygotes. There are 356 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00060 (1 hom. 347 hem.)
• Consequence: RAB40A NM_080879.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

Genes affected

RAB40A (HGNC:18283): (RAB40A, member RAS oncogene family) 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. [provided by RefSeq, Apr 2010]

LL0XNC01-250H12.3 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05337599).
• BP6: Variant X-103500110-C-A is Benign according to our data. Variant chrX-103500110-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2332633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 9 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080879.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB40A	NM_080879.3	MANE Select	c.647G>T	p.Ser216Ile	missense	Exon 3 of 3	NP_543155.2	Q8WXH6
	LL0XNC01-250H12.3	NR_188433.1		n.1780C>A		non_coding_transcript_exon	Exon 9 of 9
	LL0XNC01-250H12.3	NR_188435.1		n.1707C>A		non_coding_transcript_exon	Exon 9 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB40A	ENST00000304236.2	TSL:2 MANE Select	c.647G>T	p.Ser216Ile	missense	Exon 3 of 3	ENSP00000305648.1	Q8WXH6
	RAB40A	ENST00000372633.1	TSL:6	c.647G>T	p.Ser216Ile	missense	Exon 1 of 1	ENSP00000361716.1	Q8WXH6
	RAB40A	ENST00000905301.1		c.647G>T	p.Ser216Ile	missense	Exon 4 of 4	ENSP00000575360.1

Frequencies

GnomAD3 genomes AF: 0.000445 AC: 50 AN: 112479 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000732

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 24 AN: 183475 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000216

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000598 AC: 656 AN: 1097050 Hom.: 1 Cov.: 33 AF XY: 0.000955 AC XY: 347 AN XY: 363514

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000152 AC: 4 AN: 26395

American (AMR) AF: 0.000114 AC: 4 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.000298 AC: 9 AN: 30200

South Asian (SAS) AF: 0.000536 AC: 29 AN: 54125

European-Finnish (FIN) AF: 0.000321 AC: 13 AN: 40526

Middle Eastern (MID) AF: 0.00485 AC: 20 AN: 4126

European-Non Finnish (NFE) AF: 0.000671 AC: 564 AN: 841019

Other (OTH) AF: 0.000282 AC: 13 AN: 46076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000444 AC: 50 AN: 112535 Hom.: 0 Cov.: 23 AF XY: 0.000259 AC XY: 9 AN XY: 34701

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000290 AC: 9 AN: 31020

American (AMR) AF: 0.00 AC: 0 AN: 10708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.000282 AC: 1 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2722

European-Finnish (FIN) AF: 0.000162 AC: 1 AN: 6189

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000732 AC: 39 AN: 53267

Other (OTH) AF: 0.00 AC: 0 AN: 1528

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000476286), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000790 Hom.: 6

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.090
DANN	Benign	0.39
DEOGEN2	Benign	0.0020	T
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.050	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		2.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.11
Sift	Benign	0.38	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.067
MVP		0.58
MPC		0.94
ClinPred		0.013	T
GERP RS		-0.45
Varity_R		0.051
gMVP		0.087
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200647197; hg19: chrX-102755038;