rs4526212

Variant names:

• chr6-135483493-C-A
• rs4526212
• NM_001134831.2:c.135+7130G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000265602.11(AHI1):​c.135+7130G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,038 control chromosomes in the GnomAD database, including 7,817 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 0.32 (7817 hom., cov: 32)
• Consequence: AHI1 ENST00000265602.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.401
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265602.11. 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.135+7130G>T		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.135+7130G>T		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.135+7130G>T		intron	N/A	NP_001337432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.135+7130G>T		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.135+7130G>T		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.135+7130G>T		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47878 AN: 151920 Hom.: 7814 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.322

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.315 AC: 47898 AN: 152038 Hom.: 7817 Cov.: 32 AF XY: 0.313 AC XY: 23286 AN XY: 74324

African (AFR) AF: 0.229 AC: 9487 AN: 41456

American (AMR) AF: 0.317 AC: 4837 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1266 AN: 3468

East Asian (EAS) AF: 0.322 AC: 1663 AN: 5170

South Asian (SAS) AF: 0.420 AC: 2022 AN: 4820

European-Finnish (FIN) AF: 0.295 AC: 3112 AN: 10562

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24474 AN: 67964

Other (OTH) AF: 0.324 AC: 684 AN: 2112

Alfa AF: 0.333 Hom.: 1021

Bravo AF: 0.311

Asia WGS AF: 0.320 AC: 1111 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.35
PhyloP100		0.40
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: rs4526212; hg19: chr6-135804631;