rs4896142

Variant names:

• chr6-135301681-T-G
• rs4896142
• NM_001134831.2:c.3427-1123A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017651.5(AHI1):​c.3427-1123A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 985,174 control chromosomes in the GnomAD database, including 108,675 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (26493 hom., cov: 33)
  • Exomes 𝑓: 0.44 (82182 hom.)
• Consequence: AHI1 NM_017651.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.164
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.3427-1123A>C		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.3427-1123A>C		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.3427-1123A>C		intron	N/A	NP_001337432.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.3427-1123A>C		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.3427-1123A>C		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.3427-1123A>C		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83411 AN: 152042 Hom.: 26430 Cov.: 33

Gnomad AFR AF: 0.884

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.527

GnomAD4 exome AF: 0.438 AC: 365077 AN: 833016 Hom.: 82182 Cov.: 33 AF XY: 0.437 AC XY: 167952 AN XY: 384674

African (AFR) AF: 0.917 AC: 14481 AN: 15786

American (AMR) AF: 0.399 AC: 393 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 2339 AN: 5152

East Asian (EAS) AF: 0.422 AC: 1531 AN: 3630

South Asian (SAS) AF: 0.440 AC: 7243 AN: 16454

European-Finnish (FIN) AF: 0.442 AC: 122 AN: 276

Middle Eastern (MID) AF: 0.410 AC: 665 AN: 1620

European-Non Finnish (NFE) AF: 0.428 AC: 325867 AN: 761818

Other (OTH) AF: 0.456 AC: 12436 AN: 27296

GnomAD4 genome AF: 0.549 AC: 83531 AN: 152158 Hom.: 26493 Cov.: 33 AF XY: 0.542 AC XY: 40338 AN XY: 74414

African (AFR) AF: 0.884 AC: 36721 AN: 41528

American (AMR) AF: 0.462 AC: 7064 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3470

East Asian (EAS) AF: 0.412 AC: 2133 AN: 5176

South Asian (SAS) AF: 0.455 AC: 2190 AN: 4816

European-Finnish (FIN) AF: 0.338 AC: 3574 AN: 10582

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28846 AN: 67984

Other (OTH) AF: 0.533 AC: 1124 AN: 2110

Alfa AF: 0.463 Hom.: 22227

Bravo AF: 0.572

Asia WGS AF: 0.490 AC: 1703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.70
PhyloP100		-0.16
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: rs4896142; hg19: chr6-135622819;