NM_001134831.2:c.1267C>G

Variant names:

• chr6-135455811-G-C
• rs777668842
• NM_001134831.2:c.1267C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001134831.2(AHI1):​c.1267C>G​(p.Gln423Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q423R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 4 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

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.1267C>G	p.Gln423Glu	missense	Exon 10 of 29	NP_001128303.1
	AHI1	NM_001134830.2		c.1267C>G	p.Gln423Glu	missense	Exon 8 of 27	NP_001128302.1
	AHI1	NM_001350503.2		c.1267C>G	p.Gln423Glu	missense	Exon 10 of 29	NP_001337432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.1267C>G	p.Gln423Glu	missense	Exon 10 of 29	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.1267C>G	p.Gln423Glu	missense	Exon 8 of 27	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.1267C>G	p.Gln423Glu	missense	Exon 9 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 229968 AF XY: 0.00000806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448886 Hom.: 0 Cov.: 30 AF XY: 0.00000556 AC XY: 4 AN XY: 719452

African (AFR) AF: 0.00 AC: 0 AN: 33274

American (AMR) AF: 0.00 AC: 0 AN: 43438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.0000477 AC: 4 AN: 83776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104758

Other (OTH) AF: 0.00 AC: 0 AN: 59896

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Benign	0.24	T
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.49		Loss of sheet (P = 0.0228)
MVP		0.73
MPC		0.17
ClinPred		0.71	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.42
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777668842; hg19: chr6-135776949;