chr6-135465901-G-A

Variant names:

• chr6-135465901-G-A
• rs863225138
• NM_001134831.2:c.662C>T

Variant summary

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

The ENST00000265602.11(AHI1):​c.662C>T​(p.Ser221Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,436,162 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. Synonymous variant affecting the same amino acid position (i.e. S221S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AHI1 ENST00000265602.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• 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: 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=0.14535645).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265602.11. 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.662C>T	p.Ser221Leu	missense	Exon 7 of 29	NP_001128303.1
	AHI1	NM_001134830.2		c.662C>T	p.Ser221Leu	missense	Exon 5 of 27	NP_001128302.1
	AHI1	NM_001350503.2		c.662C>T	p.Ser221Leu	missense	Exon 7 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.662C>T	p.Ser221Leu	missense	Exon 7 of 29	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.662C>T	p.Ser221Leu	missense	Exon 5 of 27	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.662C>T	p.Ser221Leu	missense	Exon 6 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233274 AF XY: 0.00000791

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: 0.00000209 AC: 3 AN: 1436162 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 712010

African (AFR) AF: 0.00 AC: 0 AN: 32262

American (AMR) AF: 0.00 AC: 0 AN: 41120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 79984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1100940

Other (OTH) AF: 0.00 AC: 0 AN: 59316

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.044
Sift	Benign	0.087	T
Sift4G	Uncertain	0.036	D
Polyphen		0.0070	B
Vest4		0.17
MutPred		0.25		Loss of phosphorylation at S221 (P = 0.0288)
MVP		0.62
MPC		0.039
ClinPred		0.19	T
GERP RS		4.1
Varity_R		0.063
gMVP		0.12
Mutation Taster		=91/9	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: rs863225138; hg19: chr6-135787039;