chr6-135452010-G-A

Variant names:

• chr6-135452010-G-A
• rs1535436
• NM_001134831.2:c.1440+1331C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001134831.2(AHI1):​c.1440+1331C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 152,226 control chromosomes in the GnomAD database, including 53 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 0.024 (53 hom., cov: 32)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• Publications: 4 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=-0.91).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0242 (3677/152226) while in subpopulation AMR AF = 0.0381 (582/15290). AF 95% confidence interval is 0.0355. There are 53 homozygotes in GnomAd4. There are 1788 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AR,AD gene

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.1440+1331C>T		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.1440+1331C>T		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.1440+1331C>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.1440+1331C>T		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.1440+1331C>T		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.1440+1331C>T		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3677 AN: 152108 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00611

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0364

Gnomad OTH AF: 0.0215

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

GnomAD4 genome AF: 0.0242 AC: 3677 AN: 152226 Hom.: 53 Cov.: 32 AF XY: 0.0240 AC XY: 1788 AN XY: 74418

African (AFR) AF: 0.00612 AC: 254 AN: 41534

American (AMR) AF: 0.0381 AC: 582 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.0129 AC: 67 AN: 5178

South Asian (SAS) AF: 0.00810 AC: 39 AN: 4816

European-Finnish (FIN) AF: 0.0171 AC: 181 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0364 AC: 2473 AN: 68010

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0306 Hom.: 131

Bravo AF: 0.0239

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.48
DANN	Benign	0.45
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

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: rs1535436; hg19: chr6-135773148;