6-135442728-G-A

Variant names:

• chr6-135442728-G-A
• rs2757645
• NM_001134831.2:c.1780-14C>T

Variant summary

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

The ENST00000265602.11(AHI1):​c.1780-14C>T variant causes a intron change. The variant allele was found at a frequency of 0.916 in 1,582,822 control chromosomes in the GnomAD database, including 669,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (54399 hom., cov: 33)
  • Exomes 𝑓: 0.93 (615565 hom.)
• Consequence: AHI1 ENST00000265602.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.12
• Publications: 7 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=-0.92).
• BP6: Variant 6-135442728-G-A is Benign according to our data. Variant chr6-135442728-G-A is described in ClinVar as Benign. ClinVar VariationId is 260839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265602.11. 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.1780-14C>T		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.1780-14C>T		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.1780-14C>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.1780-14C>T		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.1780-14C>T		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.1780-14C>T		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.828 AC: 125940 AN: 152058 Hom.: 54380 Cov.: 33

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.955

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.948

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.844

GnomAD2 exomes AF: 0.915 AC: 209365 AN: 228880 AF XY: 0.922

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.954

Gnomad EAS exome AF: 0.971

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.931

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.926 AC: 1324168 AN: 1430646 Hom.: 615565 Cov.: 34 AF XY: 0.927 AC XY: 658276 AN XY: 709742

African (AFR) AF: 0.545 AC: 17637 AN: 32334

American (AMR) AF: 0.911 AC: 36903 AN: 40488

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 23844 AN: 24972

East Asian (EAS) AF: 0.966 AC: 37832 AN: 39150

South Asian (SAS) AF: 0.948 AC: 75195 AN: 79292

European-Finnish (FIN) AF: 0.970 AC: 50904 AN: 52454

Middle Eastern (MID) AF: 0.931 AC: 4854 AN: 5216

European-Non Finnish (NFE) AF: 0.932 AC: 1023264 AN: 1097642

Other (OTH) AF: 0.909 AC: 53735 AN: 59098

GnomAD4 genome AF: 0.828 AC: 126009 AN: 152176 Hom.: 54399 Cov.: 33 AF XY: 0.834 AC XY: 62061 AN XY: 74412

African (AFR) AF: 0.552 AC: 22875 AN: 41474

American (AMR) AF: 0.891 AC: 13613 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 3315 AN: 3470

East Asian (EAS) AF: 0.965 AC: 5010 AN: 5190

South Asian (SAS) AF: 0.947 AC: 4576 AN: 4832

European-Finnish (FIN) AF: 0.976 AC: 10372 AN: 10624

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63331 AN: 67992

Other (OTH) AF: 0.844 AC: 1779 AN: 2108

Alfa AF: 0.889 Hom.: 15853

Bravo AF: 0.811

Asia WGS AF: 0.904 AC: 3144 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		4.1
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: rs2757645; hg19: chr6-135763866;