chr3-49368662-G-T

Variant names:

• chr3-49368662-G-T
• rs11716445
• NM_001664.4:c.157-114C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001664.4(RHOA):​c.157-114C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 930,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: RHOA NM_001664.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205
• Publications: 23 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001664.4. 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
	RHOA	NM_001664.4	MANE Select	c.157-114C>A		intron	N/A	NP_001655.1
	RHOA	NM_001313941.2		c.157-114C>A		intron	N/A	NP_001300870.1
	RHOA	NM_001313943.2		c.157-114C>A		intron	N/A	NP_001300872.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOA	ENST00000418115.6	TSL:1 MANE Select	c.157-114C>A		intron	N/A	ENSP00000400175.1
	ENSG00000290318	ENST00000704381.1		c.157-114C>A		intron	N/A	ENSP00000515884.1
	RHOA	ENST00000880080.1		c.158C>A	p.Thr53Asn	missense splice_region	Exon 3 of 6	ENSP00000550139.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000108 AC: 1 AN: 930076 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 478384

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

African (AFR) AF: 0.00 AC: 0 AN: 21392

American (AMR) AF: 0.00 AC: 0 AN: 29620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20146

East Asian (EAS) AF: 0.00 AC: 0 AN: 36458

South Asian (SAS) AF: 0.00 AC: 0 AN: 67642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4574

European-Non Finnish (NFE) AF: 0.00000152 AC: 1 AN: 657958

Other (OTH) AF: 0.00 AC: 0 AN: 42108

⚠️ 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 Cov.: 31

Alfa AF: 0.00 Hom.: 942

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.39
DANN	Benign	0.75
PhyloP100		-0.20

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: rs11716445; hg19: chr3-49406095;