chr7-122077833-CTTAC-AA

Position:

• chr7-122077833-CTTAC-AA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_005763.4(AASS):​c.2662+1_2662+5delinsTT variant causes a splice donor, splice donor 5th base, 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_donor_5th_base, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06328659 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 id is 100642.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AASS	NM_005763.4	c.2662+1_2662+5delinsTT		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000417368.7	NP_005754.2
AASS	XM_011515725.3	c.2566+1_2566+5delinsTT		splice_donor_variant, splice_donor_5th_base_variant, intron_variant			XP_011514027.1
AASS	XM_047419710.1			downstream_gene_variant			XP_047275666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AASS	ENST00000417368.7	c.2662+1_2662+5delinsTT		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1	NM_005763.4	ENSP00000403768	P1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperlysinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777121; hg19: chr7-121717887;