rs4896147

Variant names:

• chr6-135455977-G-A
• rs4896147
• NM_001134831.2:c.1152-51C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-135455977-G-A
• chr6-135455977-G-T

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.1152-51C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,264,824 control chromosomes in the GnomAD database, including 470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (39 hom., cov: 32)
  • Exomes 𝑓: 0.027 (431 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.536
• Publications: 0 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=-0.86).
• BP6: Variant 6-135455977-G-A is Benign according to our data. Variant chr6-135455977-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 675181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0204 (3107/152134) while in subpopulation SAS AF = 0.0388 (187/4816). AF 95% confidence interval is 0.0343. There are 39 homozygotes in GnomAd4. There are 1494 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.1152-51C>T		intron_variant	Intron 9 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.1152-51C>T		intron_variant	Intron 9 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3106 AN: 152016 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00563

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.0382

Gnomad FIN AF: 0.00813

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0245

GnomAD4 exome AF: 0.0270 AC: 30098 AN: 1112690 Hom.: 431 AF XY: 0.0269 AC XY: 14414 AN XY: 534886

African (AFR) AF: 0.00434 AC: 108 AN: 24910

American (AMR) AF: 0.0383 AC: 620 AN: 16186

Ashkenazi Jewish (ASJ) AF: 0.00285 AC: 46 AN: 16120

East Asian (EAS) AF: 0.0337 AC: 1112 AN: 32992

South Asian (SAS) AF: 0.0314 AC: 1047 AN: 33312

European-Finnish (FIN) AF: 0.0109 AC: 451 AN: 41376

Middle Eastern (MID) AF: 0.00315 AC: 12 AN: 3810

European-Non Finnish (NFE) AF: 0.0284 AC: 25496 AN: 898050

Other (OTH) AF: 0.0263 AC: 1206 AN: 45934

GnomAD4 genome AF: 0.0204 AC: 3107 AN: 152134 Hom.: 39 Cov.: 32 AF XY: 0.0201 AC XY: 1494 AN XY: 74378

African (AFR) AF: 0.00559 AC: 232 AN: 41522

American (AMR) AF: 0.0329 AC: 503 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5180

South Asian (SAS) AF: 0.0388 AC: 187 AN: 4816

European-Finnish (FIN) AF: 0.00813 AC: 86 AN: 10574

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1832 AN: 67966

Other (OTH) AF: 0.0262 AC: 55 AN: 2102

Alfa AF: 0.0229 Hom.: 4

Bravo AF: 0.0216

Asia WGS AF: 0.0570 AC: 198 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.67
PhyloP100		-0.54
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: rs4896147; hg19: chr6-135777115; COSMIC: COSV55635004;