rs786200964

chr6-135411326-CAACTGCATAAAATAA-CTTTAAAACTTTAAAAAAGTC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_001134831.2(AHI1):c.2961+7_2961+21delinsGACTTTTTTAAAGTTTTAAA variant causes a splice donor, splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_001134831.2 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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 1 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.054580897 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.5, offset of 0 (no position change), new splice context is: acaGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 6-135411327-AACTGCATAAAATAA-TTTAAAACTTTAAAAAAGTC is Benign according to our data. Variant chr6-135411327-AACTGCATAAAATAA-TTTAAAACTTTAAAAAAGTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166663.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2961+7_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+7_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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2019	This variant is associated with the following publications: (PMID: 22334370) -

Familial aplasia of the vermis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

- -

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: rs786200964; hg19: chr6-135732465;