rs6940875

Variant names:

• chr6-135394832-T-C
• NM_001134831.2:c.3053A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-135394832-T-C
• chr6-135394832-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134831.2(AHI1):​c.3053A>G​(p.Gln1018Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1018P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18899536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.3053A>G	p.Gln1018Arg	missense_variant	Exon 23 of 29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.3053A>G	p.Gln1018Arg	missense_variant	Exon 23 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial aplasia of the vermis Uncertain:1

Feb 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) performed at Invitae indicates that this missense variant is not expected to disrupt AHI1 protein function. This variant has not been reported in the literature in individuals affected with AHI1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1018 of the AHI1 protein (p.Gln1018Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;.
Eigen	Benign	0.024
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.75	.;.;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.060	T;T;T;D
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.65	P;P;P;P
Vest4		0.27
MutPred		0.22		Loss of ubiquitination at K1015 (P = 0.0259);Loss of ubiquitination at K1015 (P = 0.0259);Loss of ubiquitination at K1015 (P = 0.0259);Loss of ubiquitination at K1015 (P = 0.0259);
MVP		0.36
MPC		0.087
ClinPred		0.70	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-135715970;