NM_001134831.2:c.3015A>G

Variant names:

• chr6-135394870-T-C
• rs41287054
• NM_001134831.2:c.3015A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001134831.2(AHI1):​c.3015A>G​(p.Ser1005Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,601,256 control chromosomes in the GnomAD database, including 479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (29 hom., cov: 32)
  • Exomes 𝑓: 0.023 (450 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0700
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.006).
• BP6: Variant 6-135394870-T-C is Benign according to our data. Variant chr6-135394870-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2538/152066) while in subpopulation NFE AF = 0.0256 (1736/67884). AF 95% confidence interval is 0.0246. There are 29 homozygotes in GnomAd4. There are 1171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.3015A>G	p.Ser1005Ser	synonymous	Exon 23 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3015A>G	p.Ser1005Ser	synonymous	Exon 21 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3015A>G	p.Ser1005Ser	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.3015A>G	p.Ser1005Ser	synonymous	Exon 23 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3015A>G	p.Ser1005Ser	synonymous	Exon 21 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.3015A>G	p.Ser1005Ser	synonymous	Exon 22 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2541 AN: 151948 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0617

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0413

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0179 AC: 4110 AN: 229550 AF XY: 0.0186

Gnomad AFR exome AF: 0.00410

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0400

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0227 AC: 32841 AN: 1449190 Hom.: 450 Cov.: 31 AF XY: 0.0226 AC XY: 16255 AN XY: 719420

African (AFR) AF: 0.00396 AC: 132 AN: 33324

American (AMR) AF: 0.0146 AC: 628 AN: 43014

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 1072 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.00950 AC: 799 AN: 84064

European-Finnish (FIN) AF: 0.00857 AC: 453 AN: 52846

Middle Eastern (MID) AF: 0.0237 AC: 136 AN: 5742

European-Non Finnish (NFE) AF: 0.0256 AC: 28290 AN: 1104976

Other (OTH) AF: 0.0222 AC: 1331 AN: 59950

GnomAD4 genome AF: 0.0167 AC: 2538 AN: 152066 Hom.: 29 Cov.: 32 AF XY: 0.0158 AC XY: 1171 AN XY: 74342

African (AFR) AF: 0.00433 AC: 180 AN: 41524

American (AMR) AF: 0.0166 AC: 253 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 143 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.00575 AC: 61 AN: 10610

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0256 AC: 1736 AN: 67884

Other (OTH) AF: 0.0270 AC: 57 AN: 2108

Alfa AF: 0.0221 Hom.: 98

Bravo AF: 0.0170

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Joubert syndrome 3 (2)
-	-	1	Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.1
DANN	Benign	0.69
PhyloP100		-0.070
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs41287054; hg19: chr6-135716008;