6-135465839-G-C

Variant names:

• chr6-135465839-G-C
• rs143522987
• NM_001134831.2:c.724C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134831.2(AHI1):​c.724C>G​(p.Pro242Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000753 in 1,327,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P242S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.729
• 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, 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.117334485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.724C>G	p.Pro242Ala	missense_variant	Exon 7 of 29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.724C>G	p.Pro242Ala	missense_variant	Exon 7 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.53e-7 AC: 1 AN: 1327398 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 648034

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

African (AFR) AF: 0.00 AC: 0 AN: 29234

American (AMR) AF: 0.00 AC: 0 AN: 25136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19312

East Asian (EAS) AF: 0.00 AC: 0 AN: 37458

South Asian (SAS) AF: 0.00 AC: 0 AN: 58454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4814

European-Non Finnish (NFE) AF: 9.51e-7 AC: 1 AN: 1051008

Other (OTH) AF: 0.00 AC: 0 AN: 54458

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.13	T;T;T;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.63	.;.;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M;M;.
PhyloP100		0.73
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N;N;N;D
REVEL	Benign	0.10
Sift	Benign	0.54	T;T;T;T;D
Sift4G	Benign	0.76	T;T;T;T;.
Polyphen		0.28	B;B;B;B;.
Vest4		0.20
MutPred		0.29		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;
MVP		0.56
MPC		0.12
ClinPred		0.29	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.031
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs143522987; hg19: chr6-135786977;