rs772989270

Variant names:

• chr6-135438399-G-A
• rs772989270
• NM_001134831.2:c.2012C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_001134831.2(AHI1):​c.2012C>T​(p.Thr671Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,424,334 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T671A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.88
• Publications: 3 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, Laboratory for Molecular Medicine, ClinGen, 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001134831.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 6-135438399-G-A is Pathogenic according to our data. Variant chr6-135438399-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134831.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.2012C>T	p.Thr671Ile	missense	Exon 15 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.2012C>T	p.Thr671Ile	missense	Exon 13 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.2012C>T	p.Thr671Ile	missense	Exon 15 of 29	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.2012C>T	p.Thr671Ile	missense	Exon 15 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.2012C>T	p.Thr671Ile	missense	Exon 13 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.2012C>T	p.Thr671Ile	missense	Exon 14 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000407 AC: 58 AN: 1424334 Hom.: 0 Cov.: 30 AF XY: 0.0000369 AC XY: 26 AN XY: 704898

African (AFR) AF: 0.0000304 AC: 1 AN: 32874

American (AMR) AF: 0.00 AC: 0 AN: 40790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25288

East Asian (EAS) AF: 0.00 AC: 0 AN: 38488

South Asian (SAS) AF: 0.00 AC: 0 AN: 79982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000522 AC: 57 AN: 1090982

Other (OTH) AF: 0.00 AC: 0 AN: 58924

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome (1)
1	-	-	Joubert syndrome 3 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of disorder (P = 0.0281)
MVP		0.90
MPC		0.30
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.75
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs772989270; hg19: chr6-135759537;