6-135433333-C-T

Variant names:

• chr6-135433333-C-T
• rs737561
• NM_001134831.2:c.2037-77G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134831.2(AHI1):​c.2037-77G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,010,896 control chromosomes in the GnomAD database, including 424,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (54373 hom., cov: 32)
  • Exomes 𝑓: 0.93 (369754 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.174
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-135433333-C-T is Benign according to our data. Variant chr6-135433333-C-T is described in ClinVar as Benign. ClinVar VariationId is 1188864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2037-77G>A		intron_variant	Intron 15 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2037-77G>A		intron_variant	Intron 15 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.828 AC: 125886 AN: 152020 Hom.: 54354 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.967

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.955

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.948

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.843

GnomAD4 exome AF: 0.926 AC: 794955 AN: 858758 Hom.: 369754 AF XY: 0.928 AC XY: 406686 AN XY: 438310

African (AFR) AF: 0.547 AC: 11285 AN: 20632

American (AMR) AF: 0.910 AC: 26831 AN: 29478

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 18220 AN: 19082

East Asian (EAS) AF: 0.966 AC: 32611 AN: 33746

South Asian (SAS) AF: 0.949 AC: 55656 AN: 58672

European-Finnish (FIN) AF: 0.969 AC: 34198 AN: 35288

Middle Eastern (MID) AF: 0.930 AC: 3273 AN: 3520

European-Non Finnish (NFE) AF: 0.932 AC: 576714 AN: 618492

Other (OTH) AF: 0.908 AC: 36167 AN: 39848

GnomAD4 genome AF: 0.828 AC: 125955 AN: 152138 Hom.: 54373 Cov.: 32 AF XY: 0.834 AC XY: 62041 AN XY: 74404

African (AFR) AF: 0.551 AC: 22840 AN: 41446

American (AMR) AF: 0.890 AC: 13618 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 3315 AN: 3470

East Asian (EAS) AF: 0.965 AC: 5011 AN: 5192

South Asian (SAS) AF: 0.947 AC: 4564 AN: 4820

European-Finnish (FIN) AF: 0.976 AC: 10363 AN: 10614

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63324 AN: 67982

Other (OTH) AF: 0.842 AC: 1781 AN: 2114

Alfa AF: 0.894 Hom.: 28221

Bravo AF: 0.811

Asia WGS AF: 0.903 AC: 3135 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 3 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.071
DANN	Benign	0.17
PhyloP100		-0.17
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: rs737561; hg19: chr6-135754471;