rs117447608

Variant names:

• chr6-135318577-G-A
• rs117447608
• NM_001134831.2:c.3368C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-135318577-G-A
• chr6-135318577-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017651.5(AHI1):​c.3368C>T​(p.Ser1123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,605,928 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1123P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (49 hom.)
• Consequence: AHI1 NM_017651.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.18
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011013359).
• BP6: Variant 6-135318577-G-A is Benign according to our data. Variant chr6-135318577-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00477 (726/152316) while in subpopulation NFE AF = 0.00869 (591/68038). AF 95% confidence interval is 0.00811. There are 4 homozygotes in GnomAd4. There are 345 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017651.5. 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.3368C>T	p.Ser1123Phe	missense	Exon 26 of 29	NP_001128303.1
	AHI1	NM_001134830.2		c.3368C>T	p.Ser1123Phe	missense	Exon 24 of 27	NP_001128302.1
	AHI1	NM_001350503.2		c.3368C>T	p.Ser1123Phe	missense	Exon 26 of 29	NP_001337432.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.3368C>T	p.Ser1123Phe	missense	Exon 26 of 29	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.3368C>T	p.Ser1123Phe	missense	Exon 24 of 27	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.3368C>T	p.Ser1123Phe	missense	Exon 25 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 726 AN: 152198 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00869

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00524 AC: 1239 AN: 236492 AF XY: 0.00542

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000993

Gnomad ASJ exome AF: 0.00175

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00483

Gnomad NFE exome AF: 0.00918

Gnomad OTH exome AF: 0.00532

GnomAD4 exome AF: 0.00733 AC: 10654 AN: 1453612 Hom.: 49 Cov.: 30 AF XY: 0.00726 AC XY: 5239 AN XY: 721984

African (AFR) AF: 0.00114 AC: 38 AN: 33408

American (AMR) AF: 0.00110 AC: 48 AN: 43746

Ashkenazi Jewish (ASJ) AF: 0.00155 AC: 40 AN: 25876

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39586

South Asian (SAS) AF: 0.00220 AC: 185 AN: 83942

European-Finnish (FIN) AF: 0.00506 AC: 269 AN: 53110

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.00876 AC: 9709 AN: 1108048

Other (OTH) AF: 0.00597 AC: 359 AN: 60136

GnomAD4 genome AF: 0.00477 AC: 726 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74480

African (AFR) AF: 0.00113 AC: 47 AN: 41560

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00869 AC: 591 AN: 68038

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00710 Hom.: 9

Bravo AF: 0.00431

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00302 AC: 11

ESP6500EA AF: 0.00808 AC: 66

ExAC AF: 0.00574 AC: 693

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Joubert syndrome 3 (2)
-	-	1	Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.97	L
PhyloP100		3.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.61
MVP		0.70
MPC		0.25
ClinPred		0.013	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.25
Mutation Taster		=86/14	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: rs117447608; hg19: chr6-135639715;