rs863225134

Positions:

• chr6-135433137-T-C
• chr6-135433137-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001134831.2(AHI1):​c.2156A>G​(p.Asp719Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.48

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]

AHI1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a repeat WD 3 (size 40) in uniprot entity AHI1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001134831.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 6-135433137-T-C is Pathogenic according to our data. Variant chr6-135433137-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433137-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2156A>G	p.Asp719Gly	missense_variant	16/29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2156A>G	p.Asp719Gly	missense_variant	16/29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2016

The D719G variant has been reported previously as a homozygous variant in two siblings with Joubert syndrome and was classified as presumed causal for these individuals (Bachmann-Gagescu et al., 2015; Parisi et al., 2006). Missense variants in nearby residues (R723Q and W725R) have also been reported in the Human Gene Mutation Database in association with Joubert syndrome (Stenson et al., 2014). The D719G variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the D719G variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.061	D
MutationAssessor	Pathogenic	3.8	H;H;H;H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.60	P;P;P;P
Vest4		0.99
MutPred		0.97		Gain of MoRF binding (P = 0.0795);Gain of MoRF binding (P = 0.0795);Gain of MoRF binding (P = 0.0795);Gain of MoRF binding (P = 0.0795);
MVP		0.94
MPC		0.33
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.81
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs863225134; hg19: chr6-135754275;