6-135321618-T-C

Variant names:

• chr6-135321618-T-C
• rs2064430
• NM_001134831.2:c.3328+1544A>G

Variant summary

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

The NM_001134831.2(AHI1):​c.3328+1544A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,952 control chromosomes in the GnomAD database, including 22,326 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 0.54 (22326 hom., cov: 31)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 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.3328+1544A>G		intron	N/A	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3328+1544A>G		intron	N/A	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3328+1544A>G		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.3328+1544A>G		intron	N/A	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3328+1544A>G		intron	N/A	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.3328+1544A>G		intron	N/A	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82141 AN: 151834 Hom.: 22310 Cov.: 31

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.564

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

GnomAD4 genome AF: 0.541 AC: 82199 AN: 151952 Hom.: 22326 Cov.: 31 AF XY: 0.546 AC XY: 40517 AN XY: 74246

African (AFR) AF: 0.471 AC: 19506 AN: 41420

American (AMR) AF: 0.588 AC: 8972 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2100 AN: 3472

East Asian (EAS) AF: 0.620 AC: 3196 AN: 5156

South Asian (SAS) AF: 0.524 AC: 2523 AN: 4816

European-Finnish (FIN) AF: 0.616 AC: 6485 AN: 10534

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.551 AC: 37442 AN: 67976

Other (OTH) AF: 0.558 AC: 1179 AN: 2112

Alfa AF: 0.550 Hom.: 97931

Bravo AF: 0.540

Asia WGS AF: 0.559 AC: 1945 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.63
PhyloP100		1.0
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: rs2064430; hg19: chr6-135642756; COSMIC: COSV55624880;