rs17778438

Variant names:

• chr6-135411056-G-A
• rs17778438
• NM_001134831.2:c.2961+292C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001134831.2(AHI1):​c.2961+292C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0869 in 152,172 control chromosomes in the GnomAD database, including 823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.087 (823 hom., cov: 32)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.39
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-135411056-G-A is Benign according to our data. Variant chr6-135411056-G-A is described in ClinVar as Benign. ClinVar VariationId is 1182074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2961+292C>T		intron_variant	Intron 21 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2961+292C>T		intron_variant	Intron 21 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13235 AN: 152054 Hom.: 823 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0955

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

GnomAD4 genome AF: 0.0869 AC: 13229 AN: 152172 Hom.: 823 Cov.: 32 AF XY: 0.0890 AC XY: 6623 AN XY: 74380

African (AFR) AF: 0.0241 AC: 999 AN: 41536

American (AMR) AF: 0.0676 AC: 1034 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3470

East Asian (EAS) AF: 0.248 AC: 1277 AN: 5156

South Asian (SAS) AF: 0.0896 AC: 433 AN: 4830

European-Finnish (FIN) AF: 0.158 AC: 1667 AN: 10564

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7058 AN: 67992

Other (OTH) AF: 0.0940 AC: 199 AN: 2116

Alfa AF: 0.0948 Hom.: 2012

Bravo AF: 0.0781

Asia WGS AF: 0.129 AC: 449 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 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	-0.92
CADD	Benign	0.0060
DANN	Benign	0.29
PhyloP100		-1.4
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: rs17778438; hg19: chr6-135732194; COSMIC: COSV55634955;