6-135428544-T-C

Variant names:

• chr6-135428544-T-C
• rs13218824
• NM_001134831.2:c.2623+85A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134831.2(AHI1):​c.2623+85A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,373,918 control chromosomes in the GnomAD database, including 1,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (75 hom., cov: 32)
  • Exomes 𝑓: 0.038 (978 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.586
• Publications: 3 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=-0.81).
• BP6: Variant 6-135428544-T-C is Benign according to our data. Variant chr6-135428544-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 675205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0271 (4116/151684) while in subpopulation NFE AF = 0.0407 (2748/67574). AF 95% confidence interval is 0.0394. There are 75 homozygotes in GnomAd4. There are 2016 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 75 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2623+85A>G		intron_variant	Intron 19 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2623+85A>G		intron_variant	Intron 19 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4118 AN: 151566 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00785

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0216

GnomAD4 exome AF: 0.0375 AC: 45879 AN: 1222234 Hom.: 978 AF XY: 0.0373 AC XY: 22038 AN XY: 591520

African (AFR) AF: 0.00477 AC: 125 AN: 26216

American (AMR) AF: 0.0181 AC: 331 AN: 18306

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 326 AN: 18412

East Asian (EAS) AF: 0.0000597 AC: 2 AN: 33484

South Asian (SAS) AF: 0.00804 AC: 343 AN: 42666

European-Finnish (FIN) AF: 0.0430 AC: 1857 AN: 43212

Middle Eastern (MID) AF: 0.0138 AC: 69 AN: 5014

European-Non Finnish (NFE) AF: 0.0418 AC: 41211 AN: 984890

Other (OTH) AF: 0.0323 AC: 1615 AN: 50034

GnomAD4 genome AF: 0.0271 AC: 4116 AN: 151684 Hom.: 75 Cov.: 32 AF XY: 0.0272 AC XY: 2016 AN XY: 74168

African (AFR) AF: 0.00783 AC: 325 AN: 41522

American (AMR) AF: 0.0212 AC: 323 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 73 AN: 3454

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4826

European-Finnish (FIN) AF: 0.0465 AC: 493 AN: 10602

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0407 AC: 2748 AN: 67574

Other (OTH) AF: 0.0213 AC: 45 AN: 2108

Alfa AF: 0.0313 Hom.: 17

Bravo AF: 0.0252

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.79
PhyloP100		-0.59
Mutation Taster		=99/1	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: rs13218824; hg19: chr6-135749682;