6-135394846-C-T

Variant names:

• chr6-135394846-C-T
• rs142381345
• NM_001134831.2:c.3039G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001134831.2(AHI1):​c.3039G>A​(p.Gln1013Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,606,410 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.49
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.037).
• BP6: Variant 6-135394846-C-T is Benign according to our data. Variant chr6-135394846-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0017 (259/152138) while in subpopulation AFR AF = 0.00529 (220/41556). AF 95% confidence interval is 0.00472. There are 0 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.3039G>A	p.Gln1013Gln	synonymous	Exon 23 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3039G>A	p.Gln1013Gln	synonymous	Exon 21 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3039G>A	p.Gln1013Gln	synonymous	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.3039G>A	p.Gln1013Gln	synonymous	Exon 23 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3039G>A	p.Gln1013Gln	synonymous	Exon 21 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.3039G>A	p.Gln1013Gln	synonymous	Exon 22 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000459 AC: 109 AN: 237670 AF XY: 0.000420

Gnomad AFR exome AF: 0.00573

Gnomad AMR exome AF: 0.000423

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000208 AC: 302 AN: 1454272 Hom.: 2 Cov.: 30 AF XY: 0.000203 AC XY: 147 AN XY: 722584

African (AFR) AF: 0.00494 AC: 165 AN: 33376

American (AMR) AF: 0.000618 AC: 27 AN: 43684

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 84786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.0000325 AC: 36 AN: 1108010

Other (OTH) AF: 0.000682 AC: 41 AN: 60116

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74388

African (AFR) AF: 0.00529 AC: 220 AN: 41556

American (AMR) AF: 0.00203 AC: 31 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3460

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67920

Other (OTH) AF: 0.000951 AC: 2 AN: 2102

Alfa AF: 0.000458 Hom.: 0

Bravo AF: 0.00210

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.0
DANN	Benign	0.59
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142381345; hg19: chr6-135715984;