6-135495365-T-C

Variant names:

• chr6-135495365-T-C
• rs4896149
• NM_001134831.2:c.-55+449A>G

Variant summary

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

The NM_001134831.2(AHI1):​c.-55+449A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 152,200 control chromosomes in the GnomAD database, including 48,071 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 0.75 (48057 hom., cov: 31)
  • Exomes 𝑓: 0.97 (14 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.375
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.91 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.-55+449A>G		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.-55+2218A>G		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.-55+174A>G		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.-55+449A>G		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.-55+2218A>G		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.-55+1823A>G		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.750 AC: 114040 AN: 152054 Hom.: 48057 Cov.: 31

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.966

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.879

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.774

GnomAD4 exome AF: 0.967 AC: 29 AN: 30 Hom.: 14 Cov.: 0 AF XY: 0.964 AC XY: 27 AN XY: 28

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 22 AN: 22

Other (OTH) AF: 1.00 AC: 2 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.750 AC: 114071 AN: 152170 Hom.: 48057 Cov.: 31 AF XY: 0.758 AC XY: 56399 AN XY: 74412

African (AFR) AF: 0.325 AC: 13483 AN: 41466

American (AMR) AF: 0.852 AC: 13021 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 3268 AN: 3472

East Asian (EAS) AF: 0.905 AC: 4682 AN: 5176

South Asian (SAS) AF: 0.914 AC: 4406 AN: 4820

European-Finnish (FIN) AF: 0.956 AC: 10151 AN: 10618

Middle Eastern (MID) AF: 0.866 AC: 253 AN: 292

European-Non Finnish (NFE) AF: 0.916 AC: 62303 AN: 68022

Other (OTH) AF: 0.770 AC: 1627 AN: 2112

Alfa AF: 0.743 Hom.: 7220

Bravo AF: 0.722

Asia WGS AF: 0.829 AC: 2883 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.81
PhyloP100		0.38
PromoterAI		-0.0082	Neutral
Mutation Taster		=299/1	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: rs4896149; hg19: chr6-135816503;