rs7759971

Variant names:

• chr6-135425746-C-T
• rs7759971
• NM_001134831.2:c.2764+1421G>A

Variant summary

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

The NM_001134831.2(AHI1):​c.2764+1421G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 151,528 control chromosomes in the GnomAD database, including 7,174 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 0.30 (7174 hom., cov: 31)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 18 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 = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2764+1421G>A		intron_variant	Intron 20 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2764+1421G>A		intron_variant	Intron 20 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44850 AN: 151410 Hom.: 7171 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.296 AC: 44859 AN: 151528 Hom.: 7174 Cov.: 31 AF XY: 0.295 AC XY: 21856 AN XY: 74116

African (AFR) AF: 0.162 AC: 6722 AN: 41436

American (AMR) AF: 0.312 AC: 4747 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1256 AN: 3454

East Asian (EAS) AF: 0.333 AC: 1718 AN: 5162

South Asian (SAS) AF: 0.417 AC: 2002 AN: 4806

European-Finnish (FIN) AF: 0.293 AC: 3098 AN: 10562

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24310 AN: 67600

Other (OTH) AF: 0.313 AC: 659 AN: 2108

Alfa AF: 0.311 Hom.: 1141

Bravo AF: 0.289

Asia WGS AF: 0.316 AC: 1097 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.38
PhyloP100		-1.7
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: rs7759971; hg19: chr6-135746884;