rs1052502

Variant names:

• chr6-135285427-G-A
• rs1052502
• NM_001134831.2:c.*218C>T

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.*218C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 595,260 control chromosomes in the GnomAD database, including 16,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (11555 hom., cov: 32)
  • Exomes 𝑓: 0.095 (4775 hom.)
• Consequence: AHI1 NM_001134831.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.113
• Publications: 14 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, Laboratory for Molecular Medicine, ClinGen, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000234084 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-135285427-G-A is Benign according to our data. Variant chr6-135285427-G-A is described in ClinVar as Benign. ClinVar VariationId is 355491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.*218C>T		3_prime_UTR	Exon 29 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.*218C>T		3_prime_UTR	Exon 27 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.*218C>T		3_prime_UTR	Exon 29 of 29	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.*218C>T		3_prime_UTR	Exon 29 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.*218C>T		3_prime_UTR	Exon 27 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.*218C>T		3_prime_UTR	Exon 28 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39462 AN: 152024 Hom.: 11505 Cov.: 32

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0735

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.0946 AC: 41915 AN: 443118 Hom.: 4775 Cov.: 4 AF XY: 0.0914 AC XY: 21467 AN XY: 234942

African (AFR) AF: 0.717 AC: 8689 AN: 12112

American (AMR) AF: 0.112 AC: 2091 AN: 18648

Ashkenazi Jewish (ASJ) AF: 0.0563 AC: 780 AN: 13856

East Asian (EAS) AF: 0.117 AC: 3592 AN: 30664

South Asian (SAS) AF: 0.0960 AC: 4129 AN: 42992

European-Finnish (FIN) AF: 0.0296 AC: 889 AN: 29986

Middle Eastern (MID) AF: 0.0956 AC: 215 AN: 2250

European-Non Finnish (NFE) AF: 0.0688 AC: 18385 AN: 267054

Other (OTH) AF: 0.123 AC: 3145 AN: 25556

GnomAD4 genome AF: 0.260 AC: 39573 AN: 152142 Hom.: 11555 Cov.: 32 AF XY: 0.252 AC XY: 18725 AN XY: 74392

African (AFR) AF: 0.725 AC: 30088 AN: 41484

American (AMR) AF: 0.149 AC: 2272 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3470

East Asian (EAS) AF: 0.120 AC: 621 AN: 5186

South Asian (SAS) AF: 0.113 AC: 546 AN: 4824

European-Finnish (FIN) AF: 0.0252 AC: 267 AN: 10602

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0735 AC: 4998 AN: 67980

Other (OTH) AF: 0.238 AC: 501 AN: 2108

Alfa AF: 0.135 Hom.: 11875

Bravo AF: 0.291

Asia WGS AF: 0.199 AC: 694 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Joubert syndrome 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.91
DANN	Benign	0.60
PhyloP100		0.11
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: rs1052502; hg19: chr6-135606565; COSMIC: COSV55634852;