3-49368647-T-C

Variant names:

• chr3-49368647-T-C
• rs2878298
• NM_001664.4:c.157-99A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001664.4(RHOA):​c.157-99A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,272,802 control chromosomes in the GnomAD database, including 145,747 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.44 (15783 hom., cov: 30)
  • Exomes 𝑓: 0.46 (129964 hom.)
• Consequence: RHOA NM_001664.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 14 publications found

Genes affected

RHOA (HGNC:667): (ras homolog family member A) This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. Overexpression of this gene is associated with tumor cell proliferation and metastasis. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]

RHOA Gene-Disease associations (from GenCC):

• ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000290318 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOA	NM_001664.4	c.157-99A>G		intron_variant	Intron 2 of 4	ENST00000418115.6	NP_001655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOA	ENST00000418115.6	c.157-99A>G		intron_variant	Intron 2 of 4	1	NM_001664.4	ENSP00000400175.1
ENSG00000290318	ENST00000704381.1	c.157-99A>G		intron_variant	Intron 2 of 5			ENSP00000515884.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66237 AN: 151646 Hom.: 15772 Cov.: 30

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.462 AC: 518255 AN: 1121042 Hom.: 129964 AF XY: 0.469 AC XY: 266662 AN XY: 568878

African (AFR) AF: 0.332 AC: 8515 AN: 25652

American (AMR) AF: 0.693 AC: 23969 AN: 34592

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 7917 AN: 22632

East Asian (EAS) AF: 0.934 AC: 35255 AN: 37766

South Asian (SAS) AF: 0.662 AC: 49911 AN: 75396

European-Finnish (FIN) AF: 0.350 AC: 18219 AN: 51990

Middle Eastern (MID) AF: 0.403 AC: 2036 AN: 5050

European-Non Finnish (NFE) AF: 0.427 AC: 349956 AN: 819222

Other (OTH) AF: 0.461 AC: 22477 AN: 48742

GnomAD4 genome AF: 0.437 AC: 66282 AN: 151760 Hom.: 15783 Cov.: 30 AF XY: 0.443 AC XY: 32820 AN XY: 74144

African (AFR) AF: 0.342 AC: 14164 AN: 41362

American (AMR) AF: 0.578 AC: 8780 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1206 AN: 3472

East Asian (EAS) AF: 0.930 AC: 4823 AN: 5186

South Asian (SAS) AF: 0.681 AC: 3277 AN: 4812

European-Finnish (FIN) AF: 0.345 AC: 3625 AN: 10514

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.425 AC: 28886 AN: 67930

Other (OTH) AF: 0.440 AC: 924 AN: 2102

Alfa AF: 0.427 Hom.: 4957

Bravo AF: 0.452

Asia WGS AF: 0.776 AC: 2692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.9
DANN	Benign	0.64
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2878298; hg19: chr3-49406080;