7-39690405-C-G

Variant names:

• chr7-39690405-C-G
• rs2116081899
• NM_005402.4:c.138C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_005402.4(RALA):​c.138C>G​(p.Thr46Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RALA NM_005402.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.19
• Publications: 0 publications found

Genes affected

RALA (HGNC:9839): (RAS like proto-oncogene A) The product of this gene belongs to the small GTPase superfamily, Ras family of proteins. GTP-binding proteins mediate the transmembrane signaling initiated by the occupancy of certain cell surface receptors. This gene encodes a low molecular mass ras-like GTP-binding protein that shares about 50% similarity with other ras proteins. [provided by RefSeq, Jul 2008]

RALA Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• Hiatt-Neu-Cooper neurodevelopmental syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 7-39690405-C-G is Benign according to our data. Variant chr7-39690405-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1575130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005402.4. 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
	RALA	NM_005402.4	MANE Select	c.138C>G	p.Thr46Thr	synonymous	Exon 3 of 5	NP_005393.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALA	ENST00000005257.7	TSL:1 MANE Select	c.138C>G	p.Thr46Thr	synonymous	Exon 3 of 5	ENSP00000005257.2	P11233
	RALA	ENST00000860175.1		c.138C>G	p.Thr46Thr	synonymous	Exon 4 of 6	ENSP00000530234.1
	RALA	ENST00000860176.1		c.138C>G	p.Thr46Thr	synonymous	Exon 4 of 6	ENSP00000530235.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461538 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

⚠️ 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: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111792

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.62
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2116081899; hg19: chr7-39730004;