6-135290508-T-C

Variant names:

• chr6-135290508-T-C
• rs199578341
• NM_001134831.2:c.3503A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000265602.11(AHI1):​c.3503A>G​(p.Glu1168Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,613,824 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1168E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: AHI1 ENST00000265602.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 0.932
• Publications: 5 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

ENSG00000234084 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007654071).
• BP6: Variant 6-135290508-T-C is Benign according to our data. Variant chr6-135290508-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 388935.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00101 (154/152262) while in subpopulation NFE AF = 0.00199 (135/68008). AF 95% confidence interval is 0.00171. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.3503A>G	p.Glu1168Gly	missense	Exon 28 of 29	NP_001128303.1
	AHI1	NM_001134830.2		c.3503A>G	p.Glu1168Gly	missense	Exon 26 of 27	NP_001128302.1
	AHI1	NM_001350503.2		c.3503A>G	p.Glu1168Gly	missense	Exon 28 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.3503A>G	p.Glu1168Gly	missense	Exon 28 of 29	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.3503A>G	p.Glu1168Gly	missense	Exon 26 of 27	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.3503A>G	p.Glu1168Gly	missense	Exon 27 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000932 AC: 230 AN: 246704 AF XY: 0.000940

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.00217 AC: 3166 AN: 1461562 Hom.: 4 Cov.: 30 AF XY: 0.00212 AC XY: 1544 AN XY: 727062

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53362

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00273 AC: 3031 AN: 1111782

Other (OTH) AF: 0.00157 AC: 95 AN: 60366

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74454

African (AFR) AF: 0.000337 AC: 14 AN: 41540

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00199 AC: 135 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00122

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000532 AC: 2

ESP6500EA AF: 0.00303 AC: 25

ExAC AF: 0.000828 AC: 100

EpiCase AF: 0.00218

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Joubert syndrome 3 (3)
-	1	1	not provided (2)
-	-	1	AHI1-related disorder (1)
-	1	-	Intellectual disability (1)
-	-	1	Joubert syndrome (1)
-	-	1	not specified (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.93
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.034
Sift	Benign	0.098	T
Sift4G	Benign	0.17	T
Polyphen		0.42	B
Vest4		0.21
MVP		0.57
MPC		0.046
ClinPred		0.013	T
GERP RS		3.4
Varity_R		0.065
gMVP		0.29
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199578341; hg19: chr6-135611646; COSMIC: COSV106081171;