1-38856996-GG-AT

Variant names:

• chr1-38856996-GG-AT
• NM_022157.4:c.323_324delCCinsAT
• RRAGC p.Ser108Tyr

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_022157.4(RRAGC):​c.323_324delCCinsAT​(p.Ser108Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S108F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRAGC NM_022157.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

RRAGC (HGNC:19902): (Ras related GTP binding C) This gene encodes a member of the GTR/RAG GTP-binding protein family. The encoded protein is a monomeric guanine nucleotide-binding protein which forms a heterodimer with RRAGA and RRAGB and is primarily localized to the cytoplasm. The encoded protein promotes intracellular localization of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

RRAGC Gene-Disease associations (from GenCC):

• Long-Olsen-Distelmaier syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, PanelApp Australia

ENSG00000273637 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.4643 (below the threshold of 3.09). Trascript score misZ: 1.8441 (below the threshold of 3.09). GenCC associations: The gene is linked to Long-Olsen-Distelmaier syndrome.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022157.4. 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
	RRAGC	NM_022157.4	MANE Select	c.323_324delCCinsAT	p.Ser108Tyr	missense	N/A	NP_071440.1	Q9HB90
	RRAGC	NM_001271851.2		c.238-17_238-16delCCinsAT		intron	N/A	NP_001258780.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAGC	ENST00000373001.4	TSL:1 MANE Select	c.323_324delCCinsAT	p.Ser108Tyr	missense	N/A	ENSP00000362092.3	Q9HB90
	RRAGC	ENST00000865048.1		c.323_324delCCinsAT	p.Ser108Tyr	missense	N/A	ENSP00000535107.1
	RRAGC	ENST00000865049.1		c.323_324delCCinsAT	p.Ser108Tyr	missense	N/A	ENSP00000535108.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-39322668;