6-135302695-C-T

Variant names:

• chr6-135302695-C-T
• rs2207000
• NM_001134831.2:c.3427-2137G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001134831.2(AHI1):​c.3427-2137G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,215,734 control chromosomes in the GnomAD database, including 29,017 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (7052 hom., cov: 32)
  • Exomes 𝑓: 0.20 (21965 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 31 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

ENSG00000234084 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

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.3427-2137G>A		intron	N/A	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3427-2137G>A		intron	N/A	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3427-2137G>A		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.3427-2137G>A		intron	N/A	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3427-2137G>A		intron	N/A	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.3427-2137G>A		intron	N/A	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41164 AN: 151930 Hom.: 7027 Cov.: 32

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.197 AC: 209058 AN: 1063686 Hom.: 21965 Cov.: 34 AF XY: 0.195 AC XY: 100709 AN XY: 517426

African (AFR) AF: 0.514 AC: 10819 AN: 21034

American (AMR) AF: 0.127 AC: 1768 AN: 13942

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 2506 AN: 11900

East Asian (EAS) AF: 0.111 AC: 1243 AN: 11234

South Asian (SAS) AF: 0.128 AC: 8038 AN: 62788

European-Finnish (FIN) AF: 0.188 AC: 1924 AN: 10252

Middle Eastern (MID) AF: 0.211 AC: 805 AN: 3822

European-Non Finnish (NFE) AF: 0.196 AC: 174140 AN: 890554

Other (OTH) AF: 0.205 AC: 7815 AN: 38160

GnomAD4 genome AF: 0.271 AC: 41238 AN: 152048 Hom.: 7052 Cov.: 32 AF XY: 0.265 AC XY: 19702 AN XY: 74330

African (AFR) AF: 0.484 AC: 20055 AN: 41428

American (AMR) AF: 0.194 AC: 2970 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 713 AN: 3468

East Asian (EAS) AF: 0.111 AC: 578 AN: 5192

South Asian (SAS) AF: 0.136 AC: 654 AN: 4822

European-Finnish (FIN) AF: 0.184 AC: 1944 AN: 10568

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13578 AN: 67958

Other (OTH) AF: 0.277 AC: 585 AN: 2112

Alfa AF: 0.218 Hom.: 8877

Bravo AF: 0.281

Asia WGS AF: 0.162 AC: 565 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs2207000; hg19: chr6-135623833;