chr6-135442447-T-C

Variant names:

• chr6-135442447-T-C
• rs2614274
• NM_001134831.2:c.1912+135A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001134831.2(AHI1):​c.1912+135A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.984 in 960,342 control chromosomes in the GnomAD database, including 465,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.99 (74315 hom., cov: 33)
  • Exomes 𝑓: 0.98 (391035 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.706
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-135442447-T-C is Benign according to our data. Variant chr6-135442447-T-C is described in ClinVar as Benign. ClinVar VariationId is 1246420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.1912+135A>G		intron_variant	Intron 14 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.1912+135A>G		intron_variant	Intron 14 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.988 AC: 150336 AN: 152208 Hom.: 74257 Cov.: 33

Gnomad AFR AF: 0.995

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 0.992

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.994

Gnomad FIN AF: 0.988

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.980

Gnomad OTH AF: 0.989

GnomAD4 exome AF: 0.984 AC: 794909 AN: 808016 Hom.: 391035 AF XY: 0.984 AC XY: 387075 AN XY: 393452

African (AFR) AF: 0.997 AC: 17867 AN: 17912

American (AMR) AF: 0.993 AC: 11799 AN: 11882

Ashkenazi Jewish (ASJ) AF: 0.990 AC: 13696 AN: 13828

East Asian (EAS) AF: 1.00 AC: 28894 AN: 28894

South Asian (SAS) AF: 0.994 AC: 21564 AN: 21700

European-Finnish (FIN) AF: 0.984 AC: 35661 AN: 36224

Middle Eastern (MID) AF: 0.991 AC: 2744 AN: 2770

European-Non Finnish (NFE) AF: 0.982 AC: 627519 AN: 639182

Other (OTH) AF: 0.987 AC: 35165 AN: 35624

GnomAD4 genome AF: 0.988 AC: 150453 AN: 152326 Hom.: 74315 Cov.: 33 AF XY: 0.988 AC XY: 73596 AN XY: 74484

African (AFR) AF: 0.995 AC: 41368 AN: 41574

American (AMR) AF: 0.994 AC: 15207 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.992 AC: 3443 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5188

South Asian (SAS) AF: 0.994 AC: 4802 AN: 4830

European-Finnish (FIN) AF: 0.988 AC: 10490 AN: 10620

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.980 AC: 66663 AN: 68024

Other (OTH) AF: 0.989 AC: 2091 AN: 2114

Alfa AF: 0.974 Hom.: 3894

Bravo AF: 0.989

Asia WGS AF: 0.997 AC: 3466 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 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	-0.90
CADD	Benign	0.72
DANN	Benign	0.60
PhyloP100		-0.71
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: rs2614274; hg19: chr6-135763585;