chr6-135497680-C-T

Variant names:

• chr6-135497680-C-T
• rs113052089
• NM_001134831.2:c.-299G>A

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.-299G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 163,520 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (146 hom., cov: 33)
  • Exomes 𝑓: 0.036 (10 hom.)
• Consequence: AHI1 NM_001134831.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.881
• 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-DT (HGNC:32526): (AHI1 divergent transcript)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-135497680-C-T is Benign according to our data. Variant chr6-135497680-C-T is described in ClinVar as Benign. ClinVar VariationId is 355514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0349 (5316/152366) while in subpopulation AMR AF = 0.0479 (733/15310). AF 95% confidence interval is 0.045. There are 146 homozygotes in GnomAd4. There are 2627 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 146 AR,AD gene

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.-299G>A		5_prime_UTR	Exon 1 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.-152G>A		5_prime_UTR	Exon 1 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.-408G>A		5_prime_UTR	Exon 1 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.-299G>A		5_prime_UTR	Exon 1 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.-152G>A		5_prime_UTR	Exon 1 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.-214G>A		5_prime_UTR	Exon 1 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5317 AN: 152250 Hom.: 146 Cov.: 33

Gnomad AFR AF: 0.00902

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0479

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.0716

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0359 AC: 400 AN: 11154 Hom.: 10 Cov.: 0 AF XY: 0.0354 AC XY: 251 AN XY: 7084

African (AFR) AF: 0.00 AC: 0 AN: 60

American (AMR) AF: 0.00 AC: 0 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 2 AN: 180

East Asian (EAS) AF: 0.00 AC: 0 AN: 26

South Asian (SAS) AF: 0.0291 AC: 116 AN: 3984

European-Finnish (FIN) AF: 0.0476 AC: 44 AN: 924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 18

European-Non Finnish (NFE) AF: 0.0411 AC: 227 AN: 5526

Other (OTH) AF: 0.0257 AC: 11 AN: 428

GnomAD4 genome AF: 0.0349 AC: 5316 AN: 152366 Hom.: 146 Cov.: 33 AF XY: 0.0353 AC XY: 2627 AN XY: 74514

African (AFR) AF: 0.00899 AC: 374 AN: 41596

American (AMR) AF: 0.0479 AC: 733 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0277 AC: 134 AN: 4834

European-Finnish (FIN) AF: 0.0716 AC: 761 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0463 AC: 3151 AN: 68022

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0405 Hom.: 14

Bravo AF: 0.0339

Asia WGS AF: 0.0140 AC: 49 AN: 3476

ClinVar

ClinVar submissions

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	-0.72
CADD	Benign	7.3
DANN	Benign	0.87
PhyloP100		-0.88
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs113052089; hg19: chr6-135818818;