rs863225133

Positions:

• chr6-135457530-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001134831.2(AHI1):​c.1115A>G​(p.Asp372Gly) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.26

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 6-135457530-T-C is Pathogenic according to our data. Variant chr6-135457530-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 217529.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-135457530-T-C is described in Lovd as [Pathogenic]. Variant chr6-135457530-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.1115A>G	p.Asp372Gly	missense_variant	9/29	ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.1115A>G	p.Asp372Gly	missense_variant	9/29	1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	3.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.99
MutPred		0.52		Loss of catalytic residue at D372 (P = 0.011);Loss of catalytic residue at D372 (P = 0.011);Loss of catalytic residue at D372 (P = 0.011);Loss of catalytic residue at D372 (P = 0.011);
MVP		0.82
MPC		0.32
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.72
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs863225133; hg19: chr6-135778668;