6-135435884-A-G

Variant names:

• chr6-135435884-A-G
• rs1535435
• NM_001134831.2:c.2036+2491T>C

Variant summary

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

The NM_001134831.2(AHI1):​c.2036+2491T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 152,090 control chromosomes in the GnomAD database, including 48,984 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 0.77 (48984 hom., cov: 31)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120
• Publications: 7 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.908 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.2036+2491T>C		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.2036+2491T>C		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.2036+2491T>C		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.2036+2491T>C		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.2036+2491T>C		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.2036+2491T>C		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116761 AN: 151972 Hom.: 48986 Cov.: 31

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.966

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.955

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.914

Gnomad OTH AF: 0.789

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

GnomAD4 genome AF: 0.768 AC: 116791 AN: 152090 Hom.: 48984 Cov.: 31 AF XY: 0.775 AC XY: 57648 AN XY: 74360

African (AFR) AF: 0.391 AC: 16205 AN: 41414

American (AMR) AF: 0.860 AC: 13138 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 3258 AN: 3466

East Asian (EAS) AF: 0.911 AC: 4719 AN: 5182

South Asian (SAS) AF: 0.912 AC: 4405 AN: 4828

European-Finnish (FIN) AF: 0.955 AC: 10141 AN: 10614

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.914 AC: 62133 AN: 68000

Other (OTH) AF: 0.786 AC: 1660 AN: 2112

Alfa AF: 0.870 Hom.: 99497

Bravo AF: 0.743

Asia WGS AF: 0.833 AC: 2898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.68
PhyloP100		-0.012
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: rs1535435; hg19: chr6-135757022;