NM_001134831.2:c.3485+3304C>T

Variant names:

• chr6-135297196-G-A
• rs6933077
• NM_001134831.2:c.3485+3304C>T

Variant summary

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

The NM_001134831.2(AHI1):​c.3485+3304C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 152,034 control chromosomes in the GnomAD database, including 7,715 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 0.20 (7715 hom., cov: 32)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.903
• 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

ENSG00000234084 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134831.2. 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+3304C>T		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.3485+3304C>T		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.3485+3304C>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.3485+3304C>T		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.3485+3304C>T		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.3485+3304C>T		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29996 AN: 151916 Hom.: 7691 Cov.: 32

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.0875

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.170

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.198 AC: 30082 AN: 152034 Hom.: 7715 Cov.: 32 AF XY: 0.191 AC XY: 14229 AN XY: 74328

African (AFR) AF: 0.597 AC: 24732 AN: 41422

American (AMR) AF: 0.0943 AC: 1440 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3470

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5184

South Asian (SAS) AF: 0.0868 AC: 417 AN: 4806

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10592

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.0399 AC: 2715 AN: 67968

Other (OTH) AF: 0.172 AC: 363 AN: 2110

Alfa AF: 0.148 Hom.: 698

Bravo AF: 0.221

Asia WGS AF: 0.108 AC: 377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.58
DANN	Benign	0.59
PhyloP100		-0.90
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: rs6933077; hg19: chr6-135618334;