rs150425546

Variant names:

• chr6-135442703-G-A
• rs150425546
• NM_001134831.2:c.1791C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001134831.2(AHI1):​c.1791C>T​(p.Ile597Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,607,948 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (5 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.658
• 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 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
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.097).
• BP6: Variant 6-135442703-G-A is Benign according to our data. Variant chr6-135442703-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.658 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00299 (455/152272) while in subpopulation AFR AF = 0.00982 (408/41558). AF 95% confidence interval is 0.00903. There are 7 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1791C>T	p.Ile597Ile	synonymous	Exon 14 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.1791C>T	p.Ile597Ile	synonymous	Exon 12 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.1791C>T	p.Ile597Ile	synonymous	Exon 14 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.1791C>T	p.Ile597Ile	synonymous	Exon 14 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.1791C>T	p.Ile597Ile	synonymous	Exon 12 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.1791C>T	p.Ile597Ile	synonymous	Exon 13 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152154 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00953

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000760 AC: 185 AN: 243498 AF XY: 0.000530

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000565

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000721

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000416 AC: 606 AN: 1455676 Hom.: 5 Cov.: 30 AF XY: 0.000344 AC XY: 249 AN XY: 723832

African (AFR) AF: 0.0108 AC: 360 AN: 33312

American (AMR) AF: 0.000748 AC: 33 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.0000590 AC: 5 AN: 84702

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53156

Middle Eastern (MID) AF: 0.00337 AC: 19 AN: 5642

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1109232

Other (OTH) AF: 0.00113 AC: 68 AN: 60096

GnomAD4 genome AF: 0.00299 AC: 455 AN: 152272 Hom.: 7 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74450

African (AFR) AF: 0.00982 AC: 408 AN: 41558

American (AMR) AF: 0.00183 AC: 28 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.3
DANN	Benign	0.80
PhyloP100		0.66
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: rs150425546; hg19: chr6-135763841;