chr6-135465839-G-A

Variant names:

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

Variant summary

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

The NM_001134831.2(AHI1):​c.724C>T​(p.Pro242Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,479,658 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.729
• Publications: 3 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, Laboratory for Molecular Medicine, ClinGen, 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=0.004656881).
• BP6: Variant 6-135465839-G-A is Benign according to our data. Variant chr6-135465839-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00299 (456/152264) while in subpopulation AFR AF = 0.00984 (409/41554). AF 95% confidence interval is 0.00906. There are 7 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.724C>T	p.Pro242Ser	missense	Exon 7 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.724C>T	p.Pro242Ser	missense	Exon 5 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.724C>T	p.Pro242Ser	missense	Exon 7 of 29	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.724C>T	p.Pro242Ser	missense	Exon 7 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.724C>T	p.Pro242Ser	missense	Exon 5 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.724C>T	p.Pro242Ser	missense	Exon 6 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152146 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00956

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000969 AC: 158 AN: 163020 AF XY: 0.000667

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000777

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000607

Gnomad OTH exome AF: 0.000868

GnomAD4 exome AF: 0.000411 AC: 545 AN: 1327394 Hom.: 4 Cov.: 30 AF XY: 0.000341 AC XY: 221 AN XY: 648032

African (AFR) AF: 0.0110 AC: 321 AN: 29230

American (AMR) AF: 0.00103 AC: 26 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: 0.0000513 AC: 3 AN: 58454

European-Finnish (FIN) AF: 0.0000210 AC: 1 AN: 47524

Middle Eastern (MID) AF: 0.00395 AC: 19 AN: 4814

European-Non Finnish (NFE) AF: 0.000108 AC: 114 AN: 1051008

Other (OTH) AF: 0.00112 AC: 61 AN: 54458

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152264 Hom.: 7 Cov.: 32 AF XY: 0.00300 AC XY: 223 AN XY: 74446

African (AFR) AF: 0.00984 AC: 409 AN: 41554

American (AMR) AF: 0.00183 AC: 28 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68002

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00345

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00547 AC: 20

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00100 AC: 120

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	AHI1-related disorder (1)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.73
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.074
Sift	Benign	0.32	T
Sift4G	Benign	0.75	T
Polyphen		0.055	B
Vest4		0.20
MVP		0.54
MPC		0.052
ClinPred		0.011	T
GERP RS		5.0
Varity_R		0.038
gMVP		0.062
Mutation Taster		=100/0	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;