NM_001134831.2:c.3053A>C

Variant names:

• chr6-135394832-T-G
• rs6940875
• NM_001134831.2:c.3053A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134831.2(AHI1):​c.3053A>C​(p.Gln1018Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,608,110 control chromosomes in the GnomAD database, including 148 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. Q1018R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (69 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.67
• Publications: 9 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=0.0038753152).
• BP6: Variant 6-135394832-T-G is Benign according to our data. Variant chr6-135394832-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

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.3053A>C	p.Gln1018Pro	missense	Exon 23 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3053A>C	p.Gln1018Pro	missense	Exon 21 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3053A>C	p.Gln1018Pro	missense	Exon 23 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.3053A>C	p.Gln1018Pro	missense	Exon 23 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3053A>C	p.Gln1018Pro	missense	Exon 21 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.3053A>C	p.Gln1018Pro	missense	Exon 22 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2385 AN: 152062 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00405 AC: 973 AN: 240244 AF XY: 0.00285

Gnomad AFR exome AF: 0.0577

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000711

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00171 AC: 2491 AN: 1455930 Hom.: 69 Cov.: 30 AF XY: 0.00150 AC XY: 1087 AN XY: 723642

African (AFR) AF: 0.0584 AC: 1951 AN: 33384

American (AMR) AF: 0.00223 AC: 98 AN: 43950

Ashkenazi Jewish (ASJ) AF: 0.000655 AC: 17 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000941 AC: 8 AN: 84994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53192

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5758

European-Non Finnish (NFE) AF: 0.000191 AC: 212 AN: 1108960

Other (OTH) AF: 0.00307 AC: 185 AN: 60184

GnomAD4 genome AF: 0.0157 AC: 2388 AN: 152180 Hom.: 79 Cov.: 32 AF XY: 0.0149 AC XY: 1106 AN XY: 74420

African (AFR) AF: 0.0549 AC: 2281 AN: 41556

American (AMR) AF: 0.00419 AC: 64 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3464

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67930

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00463 Hom.: 48

Bravo AF: 0.0173

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0651 AC: 244

ESP6500EA AF: 0.000364 AC: 3

ExAC AF: 0.00476 AC: 575

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.024
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.075
Sift	Benign	0.048	D
Sift4G	Benign	0.25	T
Polyphen		0.98	D
Vest4		0.26
MVP		0.42
MPC		0.19
ClinPred		0.025	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.33
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6940875; hg19: chr6-135715970; COSMIC: COSV99039550;