chr6-135411327-AACTGCATAAAATAAA-TTTAAAACTTTAAAAAAGTC

Position:

• chr6-135411327-AACTGCATAAAATAAA-TTTAAAACTTTAAAAAAGTC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PVS1_Moderate PM2 BP6_Moderate

The NM_001134831.2(AHI1):​c.2961+6_2961+21delinsGACTTTTTTAAAGTTTTAAA variant causes a splice donor, splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_001134831.2 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63

Genes affected

AHI1 (HGNC:21575): (Abelson helper integration site 1) This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.054580897 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 0 (no position change), new splice context is: acaGTaagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 6-135411327-AACTGCATAAAATAAA-TTTAAAACTTTAAAAAAGTC is Benign according to our data. Variant chr6-135411327-AACTGCATAAAATAAA-TTTAAAACTTTAAAAAAGTC is described in ClinVar as [Likely_benign]. Clinvar id is 241184.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2961+6_2961+21delinsGACTTTTTTAAAGTTTTAAA		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.2961+6_2961+21delinsGACTTTTTTAAAGTTTTAAA		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1	NM_001134831.2	P2

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: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial aplasia of the vermis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 04, 2016

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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: rs878855030; hg19: chr6-135732465;