chr6-135490792-A-G

Variant names:

• chr6-135490792-A-G
• rs146965488
• NM_001134831.2:c.11-45T>C

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.11-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,604,500 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0760
• Publications: 0 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-135490792-A-G is Benign according to our data. Variant chr6-135490792-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 260836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00315 (480/152336) while in subpopulation AFR AF = 0.0106 (440/41566). AF 95% confidence interval is 0.00977. There are 3 homozygotes in GnomAd4. There are 229 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.11-45T>C		intron	N/A	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.11-45T>C		intron	N/A	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.11-45T>C		intron	N/A	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.11-45T>C		intron	N/A	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.11-45T>C		intron	N/A	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.11-45T>C		intron	N/A	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000867 AC: 210 AN: 242346 AF XY: 0.000677

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000567

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.000330 AC: 479 AN: 1452164 Hom.: 1 Cov.: 30 AF XY: 0.000288 AC XY: 208 AN XY: 721846

African (AFR) AF: 0.0108 AC: 357 AN: 32998

American (AMR) AF: 0.000777 AC: 34 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52254

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5720

European-Non Finnish (NFE) AF: 0.0000352 AC: 39 AN: 1107710

Other (OTH) AF: 0.000633 AC: 38 AN: 60016

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00307 AC XY: 229 AN XY: 74492

African (AFR) AF: 0.0106 AC: 440 AN: 41566

American (AMR) AF: 0.00216 AC: 33 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00402

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.59
PhyloP100		-0.076
Mutation Taster		=100/0	polymorphism

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: rs146965488; hg19: chr6-135811930;