AHI1 p.Gln1013His

Variant names:

• chr6-135394846-C-A
• NM_001134831.2:c.3039G>T
• AHI1 p.Gln1013His

Your query was ambiguous. Multiple possible variants found:

• chr6-135394846-C-A
• chr6-135394846-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001134831.2(AHI1):​c.3039G>T​(p.Gln1013His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1013Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• 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, Laboratory for Molecular Medicine, ClinGen, 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050308675).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.3039G>T	p.Gln1013His	missense	Exon 23 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3039G>T	p.Gln1013His	missense	Exon 21 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3039G>T	p.Gln1013His	missense	Exon 23 of 29	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.3039G>T	p.Gln1013His	missense	Exon 23 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3039G>T	p.Gln1013His	missense	Exon 21 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.3039G>T	p.Gln1013His	missense	Exon 22 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.97	N
REVEL	Benign	0.045
Sift	Benign	0.19	T
Sift4G	Benign	0.23	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.32
Mutation Taster		=88/12	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-135715984;