rs11964449

Variant names:

• chr6-135448551-A-G
• rs11964449
• NM_001134831.2:c.1441-76T>C

Variant summary

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

The ENST00000265602.11(AHI1):​c.1441-76T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,167,010 control chromosomes in the GnomAD database, including 2,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.077 (1096 hom., cov: 32)
  • Exomes 𝑓: 0.026 (926 hom.)
• Consequence: AHI1 ENST00000265602.11 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.305
• Publications: 2 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=-0.81).
• BP6: Variant 6-135448551-A-G is Benign according to our data. Variant chr6-135448551-A-G is described in ClinVar as Benign. ClinVar VariationId is 1258760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 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.1441-76T>C		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.1441-76T>C		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.1441-76T>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.1441-76T>C		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.1441-76T>C		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.1441-76T>C		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.0774 AC: 11775 AN: 152188 Hom.: 1096 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0534

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0679

GnomAD4 exome AF: 0.0258 AC: 26169 AN: 1014704 Hom.: 926 AF XY: 0.0253 AC XY: 12543 AN XY: 495164

African (AFR) AF: 0.227 AC: 5335 AN: 23552

American (AMR) AF: 0.0233 AC: 519 AN: 22278

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 297 AN: 15556

East Asian (EAS) AF: 0.0406 AC: 1388 AN: 34202

South Asian (SAS) AF: 0.0384 AC: 1105 AN: 28768

European-Finnish (FIN) AF: 0.0193 AC: 680 AN: 35214

Middle Eastern (MID) AF: 0.0258 AC: 104 AN: 4026

European-Non Finnish (NFE) AF: 0.0186 AC: 15080 AN: 808890

Other (OTH) AF: 0.0393 AC: 1661 AN: 42218

GnomAD4 genome AF: 0.0774 AC: 11794 AN: 152306 Hom.: 1096 Cov.: 32 AF XY: 0.0749 AC XY: 5579 AN XY: 74472

African (AFR) AF: 0.220 AC: 9122 AN: 41538

American (AMR) AF: 0.0376 AC: 576 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.0539 AC: 279 AN: 5176

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4830

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0181 AC: 1230 AN: 68036

Other (OTH) AF: 0.0667 AC: 141 AN: 2114

Alfa AF: 0.0738 Hom.: 232

Bravo AF: 0.0877

Asia WGS AF: 0.0560 AC: 197 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.82
PhyloP100		0.30
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: rs11964449; hg19: chr6-135769689;