chr6-135442761-G-A

Variant names:

• chr6-135442761-G-A
• rs17053651
• NM_001134831.2:c.1780-47C>T

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.1780-47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,512,530 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (39 hom., cov: 32)
  • Exomes 𝑓: 0.028 (582 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.394
• 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 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-135442761-G-A is Benign according to our data. Variant chr6-135442761-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0203 (3096/152212) while in subpopulation SAS AF = 0.0378 (182/4818). AF 95% confidence interval is 0.0333. There are 39 homozygotes in GnomAd4. There are 1487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.1780-47C>T		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.1780-47C>T		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.1780-47C>T		intron	N/A	NP_001337432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.1780-47C>T		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.1780-47C>T		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.1780-47C>T		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3094 AN: 152094 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00536

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.00812

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0281 AC: 5244 AN: 186644 AF XY: 0.0287

Gnomad AFR exome AF: 0.00629

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.00330

Gnomad EAS exome AF: 0.0308

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0279 AC: 37932 AN: 1360318 Hom.: 582 Cov.: 23 AF XY: 0.0279 AC XY: 18718 AN XY: 671712

African (AFR) AF: 0.00431 AC: 132 AN: 30604

American (AMR) AF: 0.0419 AC: 1525 AN: 36388

Ashkenazi Jewish (ASJ) AF: 0.00301 AC: 71 AN: 23606

East Asian (EAS) AF: 0.0343 AC: 1270 AN: 37080

South Asian (SAS) AF: 0.0348 AC: 2436 AN: 69976

European-Finnish (FIN) AF: 0.0111 AC: 550 AN: 49662

Middle Eastern (MID) AF: 0.00372 AC: 15 AN: 4030

European-Non Finnish (NFE) AF: 0.0289 AC: 30456 AN: 1052958

Other (OTH) AF: 0.0264 AC: 1477 AN: 56014

GnomAD4 genome AF: 0.0203 AC: 3096 AN: 152212 Hom.: 39 Cov.: 32 AF XY: 0.0200 AC XY: 1487 AN XY: 74410

African (AFR) AF: 0.00534 AC: 222 AN: 41544

American (AMR) AF: 0.0329 AC: 503 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.0335 AC: 174 AN: 5190

South Asian (SAS) AF: 0.0378 AC: 182 AN: 4818

European-Finnish (FIN) AF: 0.00812 AC: 86 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1835 AN: 67998

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0230 Hom.: 19

Bravo AF: 0.0215

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.66
DANN	Benign	0.75
PhyloP100		-0.39
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: rs17053651; hg19: chr6-135763899;