rs540849894

Variant names:

• chr6-135300484-TGAA-T
• rs540849894
• NM_001134831.2:c.3485+13_3485+15delTTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_017651.5(AHI1):​c.3485+13_3485+15delTTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,592,180 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (28 hom.)
• Consequence: AHI1 NM_017651.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.44
• 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

ENSG00000234084 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-135300484-TGAA-T is Benign according to our data. Variant chr6-135300484-TGAA-T is described in ClinVar as Benign. ClinVar VariationId is 260857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.004 (610/152314) while in subpopulation NFE AF = 0.00666 (453/68024). AF 95% confidence interval is 0.00615. There are 1 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR,AD gene

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+13_3485+15delTTC		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.3485+13_3485+15delTTC		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.3485+13_3485+15delTTC		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+13_3485+15delTTC		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.3485+13_3485+15delTTC		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.3485+13_3485+15delTTC		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152196 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00368 AC: 830 AN: 225608 AF XY: 0.00379

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.000639

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00247

Gnomad NFE exome AF: 0.00620

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00550 AC: 7917 AN: 1439866 Hom.: 28 AF XY: 0.00548 AC XY: 3912 AN XY: 714224

African (AFR) AF: 0.00100 AC: 33 AN: 32942

American (AMR) AF: 0.00336 AC: 141 AN: 41982

Ashkenazi Jewish (ASJ) AF: 0.000549 AC: 14 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.000161 AC: 13 AN: 80836

European-Finnish (FIN) AF: 0.00212 AC: 111 AN: 52368

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5710

European-Non Finnish (NFE) AF: 0.00664 AC: 7319 AN: 1101658

Other (OTH) AF: 0.00477 AC: 284 AN: 59544

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152314 Hom.: 1 Cov.: 31 AF XY: 0.00329 AC XY: 245 AN XY: 74480

African (AFR) AF: 0.00118 AC: 49 AN: 41564

American (AMR) AF: 0.00529 AC: 81 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00486 Hom.: 0

Bravo AF: 0.00470

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

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: rs540849894; hg19: chr6-135621622;