6-135431282-C-T

Variant names:

• chr6-135431282-C-T
• rs755688765
• NM_001134831.2:c.2299G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001134831.2(AHI1):​c.2299G>A​(p.Val767Met) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.307

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 2 ACMG points.

• PM1: In a repeat WD 4 (size 39) in uniprot entity AHI1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001134831.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10161385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2299G>A	p.Val767Met	missense_variant	Exon 17 of 29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2299G>A	p.Val767Met	missense_variant	Exon 17 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.88	.;.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;M;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.090	N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.088	T;T;T;T
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.13	B;B;B;B
Vest4		0.22
MutPred		0.56		Loss of catalytic residue at V767 (P = 0.0539);Loss of catalytic residue at V767 (P = 0.0539);Loss of catalytic residue at V767 (P = 0.0539);Loss of catalytic residue at V767 (P = 0.0539);
MVP		0.43
MPC		0.054
ClinPred		0.16	T
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.22

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: rs755688765; hg19: chr6-135752420;