6-135447144-C-T

Variant names:

• chr6-135447144-C-T
• rs35433555
• NM_001134831.2:c.1643G>A

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.1643G>A​(p.Arg548His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,572,426 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R548C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.014 (173 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.981
• Publications: 10 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=0.008803517).
• BP6: Variant 6-135447144-C-T is Benign according to our data. Variant chr6-135447144-C-T is described in ClinVar as Benign. ClinVar VariationId is 128322.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 = 0.0103 (1569/152186) while in subpopulation NFE AF = 0.0168 (1140/68008). AF 95% confidence interval is 0.016. There are 14 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.1643G>A	p.Arg548His	missense	Exon 13 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.1643G>A	p.Arg548His	missense	Exon 11 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.1643G>A	p.Arg548His	missense	Exon 13 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.1643G>A	p.Arg548His	missense	Exon 13 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.1643G>A	p.Arg548His	missense	Exon 11 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.1643G>A	p.Arg548His	missense	Exon 12 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1570 AN: 152068 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00982

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0111 AC: 2504 AN: 224582 AF XY: 0.0115

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00433

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.0000631

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.0139 AC: 19740 AN: 1420240 Hom.: 173 Cov.: 32 AF XY: 0.0138 AC XY: 9713 AN XY: 704762

African (AFR) AF: 0.00169 AC: 54 AN: 31942

American (AMR) AF: 0.00476 AC: 188 AN: 39466

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 284 AN: 24960

East Asian (EAS) AF: 0.0000781 AC: 3 AN: 38424

South Asian (SAS) AF: 0.00366 AC: 276 AN: 75494

European-Finnish (FIN) AF: 0.0137 AC: 716 AN: 52174

Middle Eastern (MID) AF: 0.00568 AC: 32 AN: 5632

European-Non Finnish (NFE) AF: 0.0161 AC: 17571 AN: 1093476

Other (OTH) AF: 0.0105 AC: 616 AN: 58672

GnomAD4 genome AF: 0.0103 AC: 1569 AN: 152186 Hom.: 14 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74410

African (AFR) AF: 0.00275 AC: 114 AN: 41526

American (AMR) AF: 0.00608 AC: 93 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00982 AC: 34 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4816

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0168 AC: 1140 AN: 68008

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0148 Hom.: 57

Bravo AF: 0.00963

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00243 AC: 9

ESP6500EA AF: 0.0178 AC: 146

ExAC AF: 0.0105 AC: 1265

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.034
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.98
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.11
Sift	Benign	0.033	D
Sift4G	Benign	0.076	T
Polyphen		0.032	B
Vest4		0.30
MPC		0.055
ClinPred		0.023	T
GERP RS		5.2
Varity_R		0.086
gMVP		0.38
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs35433555; hg19: chr6-135768282;