rs148000791

Variant names:

• chr6-135323233-T-C
• rs148000791
• NM_001134831.2:c.3257A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134831.2(AHI1):​c.3257A>G​(p.Glu1086Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,910 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:13
• Conservation: PhyloP100: 7.67
• Publications: 17 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

ENSG00000287094 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008024454).
• BP6: Variant 6-135323233-T-C is Benign according to our data. Variant chr6-135323233-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00173 (264/152290) while in subpopulation EAS AF = 0.0401 (208/5188). AF 95% confidence interval is 0.0356. There are 2 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.3257A>G	p.Glu1086Gly	missense	Exon 25 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3257A>G	p.Glu1086Gly	missense	Exon 23 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3257A>G	p.Glu1086Gly	missense	Exon 25 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.3257A>G	p.Glu1086Gly	missense	Exon 25 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3257A>G	p.Glu1086Gly	missense	Exon 23 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.3257A>G	p.Glu1086Gly	missense	Exon 24 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00377 AC: 938 AN: 249080 AF XY: 0.00349

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0451

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00150 AC: 2186 AN: 1461620 Hom.: 43 Cov.: 30 AF XY: 0.00146 AC XY: 1065 AN XY: 727088

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0436 AC: 1729 AN: 39686

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86240

European-Finnish (FIN) AF: 0.00159 AC: 85 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000146 AC: 162 AN: 1111822

Other (OTH) AF: 0.00189 AC: 114 AN: 60370

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0401 AC: 208 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68016

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00182 Hom.: 23

Bravo AF: 0.00195

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00378 AC: 457

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
1	-	3	Joubert syndrome 3 (4)
-	-	4	not provided (4)
-	-	1	Joubert syndrome (1)
-	1	-	Optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	L
PhyloP100		7.7
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.42
MVP		0.60
MPC		0.31
ClinPred		0.062	T
GERP RS		6.1
Varity_R		0.69
gMVP		0.34
Mutation Taster		=48/52	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: rs148000791; hg19: chr6-135644371; COSMIC: COSV55628168;