chr6-135300462-C-G

Variant names:

• chr6-135300462-C-G
• rs4896141
• NM_001134831.2:c.3485+38G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017651.5(AHI1):​c.3485+38G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 1,536,176 control chromosomes in the GnomAD database, including 17,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (8009 hom., cov: 32)
  • Exomes 𝑓: 0.083 (9981 hom.)
• Consequence: AHI1 NM_017651.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.340
• Publications: 5 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

ENSG00000234084 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-135300462-C-G is Benign according to our data. Variant chr6-135300462-C-G is described in ClinVar as Benign. ClinVar VariationId is 260858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017651.5. 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.3485+38G>C		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.3485+38G>C		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.3485+38G>C		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.3485+38G>C		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.3485+38G>C		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.3485+38G>C		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33232 AN: 151778 Hom.: 7980 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.0668

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.0684

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.104 AC: 19340 AN: 186302 AF XY: 0.0961

Gnomad AFR exome AF: 0.613

Gnomad AMR exome AF: 0.0905

Gnomad ASJ exome AF: 0.0442

Gnomad EAS exome AF: 0.0656

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0679

Gnomad OTH exome AF: 0.0795

GnomAD4 exome AF: 0.0828 AC: 114573 AN: 1384282 Hom.: 9981 Cov.: 28 AF XY: 0.0815 AC XY: 55703 AN XY: 683338

African (AFR) AF: 0.626 AC: 19463 AN: 31096

American (AMR) AF: 0.0972 AC: 3489 AN: 35912

Ashkenazi Jewish (ASJ) AF: 0.0451 AC: 1093 AN: 24228

East Asian (EAS) AF: 0.0820 AC: 3089 AN: 37678

South Asian (SAS) AF: 0.101 AC: 7182 AN: 70844

European-Finnish (FIN) AF: 0.0286 AC: 1435 AN: 50130

Middle Eastern (MID) AF: 0.0871 AC: 485 AN: 5566

European-Non Finnish (NFE) AF: 0.0676 AC: 72401 AN: 1071662

Other (OTH) AF: 0.104 AC: 5936 AN: 57166

GnomAD4 genome AF: 0.219 AC: 33321 AN: 151894 Hom.: 8009 Cov.: 32 AF XY: 0.212 AC XY: 15747 AN XY: 74248

African (AFR) AF: 0.603 AC: 24936 AN: 41380

American (AMR) AF: 0.128 AC: 1959 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 148 AN: 3466

East Asian (EAS) AF: 0.0668 AC: 345 AN: 5168

South Asian (SAS) AF: 0.110 AC: 530 AN: 4812

European-Finnish (FIN) AF: 0.0243 AC: 256 AN: 10532

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.0684 AC: 4650 AN: 67958

Other (OTH) AF: 0.200 AC: 422 AN: 2110

Alfa AF: 0.116 Hom.: 546

Bravo AF: 0.244

Asia WGS AF: 0.167 AC: 580 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.64
PhyloP100		0.34
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: rs4896141; hg19: chr6-135621600; COSMIC: COSV55634896; COSMIC: COSV55634896;