6-135300457-C-G

Variant names:

• chr6-135300457-C-G
• rs73776470
• NM_001134831.2:c.3485+43G>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.3485+43G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,517,256 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: AHI1 NM_017651.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-135300457-C-G is Benign according to our data. Variant chr6-135300457-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 260859.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 = 0.00223 (339/152012) while in subpopulation AFR AF = 0.00765 (317/41442). AF 95% confidence interval is 0.00696. There are 3 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.3485+43G>C		intron	N/A	NP_001128303.1
	AHI1	NM_001134830.2		c.3485+43G>C		intron	N/A	NP_001128302.1
	AHI1	NM_001350503.2		c.3485+43G>C		intron	N/A	NP_001337432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.3485+43G>C		intron	N/A	ENSP00000265602.6
	AHI1	ENST00000367800.8	TSL:1	c.3485+43G>C		intron	N/A	ENSP00000356774.4
	AHI1	ENST00000457866.6	TSL:1	c.3485+43G>C		intron	N/A	ENSP00000388650.2

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 151896 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00762

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000567 AC: 96 AN: 169176 AF XY: 0.000455

Gnomad AFR exome AF: 0.00798

Gnomad AMR exome AF: 0.000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000477

GnomAD4 exome AF: 0.000214 AC: 292 AN: 1365244 Hom.: 3 Cov.: 27 AF XY: 0.000195 AC XY: 131 AN XY: 672682

African (AFR) AF: 0.00835 AC: 253 AN: 30314

American (AMR) AF: 0.000305 AC: 10 AN: 32752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23662

East Asian (EAS) AF: 0.00 AC: 0 AN: 37126

South Asian (SAS) AF: 0.00 AC: 0 AN: 68436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49332

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061788

Other (OTH) AF: 0.000497 AC: 28 AN: 56330

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152012 Hom.: 3 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74300

African (AFR) AF: 0.00765 AC: 317 AN: 41442

American (AMR) AF: 0.00111 AC: 17 AN: 15268

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000983 Hom.: 0

Bravo AF: 0.00246

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.098
DANN	Benign	0.62
PhyloP100		-1.3
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: rs73776470; hg19: chr6-135621595;