6-135400147-G-A

Variant names:

• chr6-135400147-G-A
• rs13208164
• NM_001134831.2:c.2988+4804C>T

Variant summary

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

The NM_001134831.2(AHI1):​c.2988+4804C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 151,626 control chromosomes in the GnomAD database, including 3,195 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 0.18 (3195 hom., cov: 31)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 13 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2988+4804C>T		intron_variant	Intron 22 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2988+4804C>T		intron_variant	Intron 22 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27759 AN: 151508 Hom.: 3195 Cov.: 31

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.183 AC: 27761 AN: 151626 Hom.: 3195 Cov.: 31 AF XY: 0.183 AC XY: 13573 AN XY: 74056

African (AFR) AF: 0.0468 AC: 1936 AN: 41366

American (AMR) AF: 0.151 AC: 2304 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 688 AN: 3466

East Asian (EAS) AF: 0.162 AC: 836 AN: 5172

South Asian (SAS) AF: 0.204 AC: 979 AN: 4804

European-Finnish (FIN) AF: 0.284 AC: 2950 AN: 10400

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17507 AN: 67904

Other (OTH) AF: 0.179 AC: 375 AN: 2100

Alfa AF: 0.227 Hom.: 7564

Bravo AF: 0.165

Asia WGS AF: 0.157 AC: 545 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.75
DANN	Benign	0.61
PhyloP100		-0.0030
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: rs13208164; hg19: chr6-135721285;