chr6-135431284-C-A

Variant names:

• chr6-135431284-C-A
• rs863225139
• NM_001134831.2:c.2297G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_017651.5(AHI1):​c.2297G>T​(p.Gly766Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G766E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_017651.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.35
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Joubert syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-135431284-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017651.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.2297G>T	p.Gly766Val	missense	Exon 17 of 29	NP_001128303.1
	AHI1	NM_001134830.2		c.2297G>T	p.Gly766Val	missense	Exon 15 of 27	NP_001128302.1
	AHI1	NM_001350503.2		c.2297G>T	p.Gly766Val	missense	Exon 17 of 29	NP_001337432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.2297G>T	p.Gly766Val	missense	Exon 17 of 29	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.2297G>T	p.Gly766Val	missense	Exon 15 of 27	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.2297G>T	p.Gly766Val	missense	Exon 16 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 242218 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.74		Loss of disorder (P = 0.1401)
MVP		0.87
MPC		0.32
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.83
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs863225139; hg19: chr6-135752422; COSMIC: COSV99663031;