rs587777121

Variant names:

• chr7-122077833-CTTAC-AA
• rs587777121
• NM_005763.4:c.2662+1_2662+5delGTAAGinsTT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_005763.4(AASS):​c.2662+1_2662+5delGTAAGinsTT variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AASS NM_005763.4 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.83
• Publications: 0 publications found

Genes affected

AASS (HGNC:17366): (aminoadipate-semialdehyde synthase) This gene encodes a bifunctional enzyme that catalyzes the first two steps in the mammalian lysine degradation pathway. The N-terminal and the C-terminal portions of this enzyme contain lysine-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Mutations in this gene are associated with familial hyperlysinemia. [provided by RefSeq, Jul 2008]

AASS Gene-Disease associations (from GenCC):

• hyperlysinemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06364617 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of 21, new splice context is: ggtGTaagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-122077833-CTTAC-AA is Pathogenic according to our data. Variant chr7-122077833-CTTAC-AA is described in ClinVar as Pathogenic. ClinVar VariationId is 100642.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005763.4. 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
	AASS	NM_005763.4	MANE Select	c.2662+1_2662+5delGTAAGinsTT		splice_donor splice_region intron	N/A	NP_005754.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AASS	ENST00000417368.7	TSL:1 MANE Select	c.2662+1_2662+5delGTAAGinsTT		splice_donor splice_region intron	N/A	ENSP00000403768.2	Q9UDR5
	AASS	ENST00000393376.5	TSL:1	c.2662+1_2662+5delGTAAGinsTT		splice_donor splice_region intron	N/A	ENSP00000377040.1	Q9UDR5
	AASS	ENST00000358954.6	TSL:1	n.*567+1_*567+5delGTAAGinsTT		splice_donor splice_region intron	N/A	ENSP00000351834.2	F8WAH1

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

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperlysinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=1/99	disease causing

Splicing

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

Other links and lift over

dbSNP: rs587777121; hg19: chr7-121717887;