rs756276537

chr6-135433188-G-Achr6-135433188-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001134831.2(AHI1):c.2105C>T(p.Thr702Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,612,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T702T) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.85

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a repeat WD 3 (size 40) in uniprot entity AHI1_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_001134831.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 6-135433188-G-A is Pathogenic according to our data. Variant chr6-135433188-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 568060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433188-G-A is described in Lovd as [Pathogenic]. Variant chr6-135433188-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2105C>T	p.Thr702Met	missense_variant	16/29	ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.2105C>T	p.Thr702Met	missense_variant	16/29	1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 248760 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 134946

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460556 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000501 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2023

Observed in several individuals with a pathogenic variant in unrelated patients with Joubert syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes these cases (Enokizono et al., 2017; Summers et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27493482, 28497568, 28125082, 28431631, 27434533, 30464253, 34627237, 15467982) -

Joubert syndrome and related disorders Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 02, 2022

Variant summary: AHI1 c.2105C>T (p.Thr702Met) results in a non-conservative amino acid change located in the WD40/YVTN repeat-like-containing domain (IPR015943) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248760 control chromosomes (gnomAD). c.2105C>T has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders (examples: Suzuki_2016, Vilboux_2017, Enokizono_2017, Summers_2017 and Chen_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Familial aplasia of the vermis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 702 of the AHI1 protein (p.Thr702Met). This variant is present in population databases (rs756276537, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 28431631, 34627237; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 568060). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AHI1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.89
MutPred		0.65		Gain of ubiquitination at K704 (P = 0.0708);Gain of ubiquitination at K704 (P = 0.0708);Gain of ubiquitination at K704 (P = 0.0708);Gain of ubiquitination at K704 (P = 0.0708);
MVP		0.82
MPC		0.30
ClinPred		0.85	D
GERP RS		5.6
Varity_R		0.24
gMVP		0.52

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: rs756276537; hg19: chr6-135754326;