6-135497752-G-C

Variant names:

• chr6-135497752-G-C
• rs533416517
• ENST00000457866.6:c.-286C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000457866.6(AHI1):​c.-286C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 197,546 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: AHI1 ENST00000457866.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 1 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-DT (HGNC:32526): (AHI1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000131 (20/152356) while in subpopulation SAS AF = 0.00414 (20/4832). AF 95% confidence interval is 0.00274. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000457866.6. 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.-371C>G		upstream_gene	N/A	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.-224C>G		upstream_gene	N/A	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.-480C>G		upstream_gene	N/A	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000457866.6	TSL:1	c.-286C>G		5_prime_UTR	Exon 1 of 28	ENSP00000388650.2	Q8N157-1
	AHI1	ENST00000681022.1		c.-2268C>G		5_prime_UTR	Exon 1 of 27	ENSP00000505121.1	Q8N157-1
	AHI1	ENST00000681340.1		c.-457C>G		5_prime_UTR	Exon 1 of 29	ENSP00000505666.1	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 668 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00164 AC: 74 AN: 45190 Hom.: 2 Cov.: 0 AF XY: 0.00218 AC XY: 61 AN XY: 28042

African (AFR) AF: 0.00 AC: 0 AN: 240

American (AMR) AF: 0.00 AC: 0 AN: 316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 890

East Asian (EAS) AF: 0.00 AC: 0 AN: 120

South Asian (SAS) AF: 0.00467 AC: 74 AN: 15850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22632

Other (OTH) AF: 0.00 AC: 0 AN: 1640

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.61
PhyloP100		2.0
PromoterAI		0.25	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs533416517; hg19: chr6-135818890;