NM_001134831.2:c.3165+42G>C

Variant names:

• chr6-135358090-C-G
• rs7772864
• NM_001134831.2:c.3165+42G>C

Variant summary

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

The NM_001134831.2(AHI1):​c.3165+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,583,260 control chromosomes in the GnomAD database, including 1,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (831 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (683 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07
• 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=-0.85).
• BP6: Variant 6-135358090-C-G is Benign according to our data. Variant chr6-135358090-C-G is described in ClinVar as Benign. ClinVar VariationId is 260855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.3165+42G>C		intron_variant	Intron 24 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.3165+42G>C		intron_variant	Intron 24 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8712 AN: 152054 Hom.: 826 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0146 AC: 3543 AN: 242974 AF XY: 0.0112

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.000340

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00933

GnomAD4 exome AF: 0.00621 AC: 8890 AN: 1431088 Hom.: 683 Cov.: 25 AF XY: 0.00541 AC XY: 3861 AN XY: 713346

African (AFR) AF: 0.196 AC: 6362 AN: 32526

American (AMR) AF: 0.0148 AC: 641 AN: 43336

Ashkenazi Jewish (ASJ) AF: 0.000463 AC: 12 AN: 25892

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39240

South Asian (SAS) AF: 0.000551 AC: 46 AN: 83500

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53270

Middle Eastern (MID) AF: 0.0149 AC: 85 AN: 5710

European-Non Finnish (NFE) AF: 0.000733 AC: 798 AN: 1088284

Other (OTH) AF: 0.0158 AC: 939 AN: 59330

GnomAD4 genome AF: 0.0574 AC: 8740 AN: 152172 Hom.: 831 Cov.: 33 AF XY: 0.0559 AC XY: 4160 AN XY: 74392

African (AFR) AF: 0.195 AC: 8103 AN: 41492

American (AMR) AF: 0.0295 AC: 451 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68004

Other (OTH) AF: 0.0502 AC: 106 AN: 2110

Alfa AF: 0.00709 Hom.: 11

Bravo AF: 0.0660

Asia WGS AF: 0.0290 AC: 100 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.56
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7772864; hg19: chr6-135679228;