Genetic Variant ERAL1:c.489+146_489+147delTT (chr17-28856714-CTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005702.4(ERAL1):c.489+146_489+147delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 576,606 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 30)

Exomes 𝑓: 0.022 ( 0 hom. )

Consequence

ERAL1
NM_005702.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0390

Publications

0 publications found

Variant links:

Genes affected

ERAL1 (HGNC:3424): (Era like 12S mitochondrial rRNA chaperone 1) The protein encoded by this gene is a GTPase that localizes to the mitochondrion. The encoded protein binds to the 3' terminal stem loop of 12S mitochondrial rRNA and is required for proper assembly of the 28S small mitochondrial ribosomal subunit. Deletion of this gene has been shown to cause mitochondrial dysfunction, growth retardation, and apoptosis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

ERAL1 Gene-Disease associations (from GenCC):

Perrault syndrome 6
Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
Perrault syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ERAL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the MID (0.0213) population. However there is too low homozygotes in high coverage region: (expected more than 40, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERAL1	NM_005702.4 link	c.489+146_489+147delTT	intron_variant	Intron 3 of 9	ENST00000254928.10	NP_005693.1	O75616-1
ERAL1	NM_001317985.2 link	c.486+149_486+150delTT	intron_variant	Intron 3 of 9		NP_001304914.1	O75616
ERAL1	NM_001317986.2 link	c.489+146_489+147delTT	intron_variant	Intron 3 of 8		NP_001304915.1	O75616
ERAL1	NR_134328.2 link	n.508+146_508+147delTT	intron_variant	Intron 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERAL1	ENST00000254928.10 link	c.489+133_489+134delTT		intron_variant	Intron 3 of 9	1	NM_005702.4	ENSP00000254928.5		O75616-1

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

137974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000793

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000731

Gnomad ASJ

AF:

0.000607

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00136

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000238

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0229

AC:

1004

AN:

43754

AF XY:

0.0224

show subpopulations

Gnomad AFR exome

AF:

0.0225

Gnomad AMR exome

AF:

0.0237

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.0259

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0218

AC:

9574

AN:

438632

Hom.:

AF XY:

0.0215

AC XY:

5000

AN XY:

232766

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0184

AC:

205

AN:

11158

American (AMR)

AF:

0.0188

AC:

323

AN:

17142

Ashkenazi Jewish (ASJ)

AF:

0.0256

AC:

307

AN:

12008

East Asian (EAS)

AF:

0.0224

AC:

548

AN:

24484

South Asian (SAS)

AF:

0.0205

AC:

857

AN:

41788

European-Finnish (FIN)

AF:

0.0246

AC:

720

AN:

29228

Middle Eastern (MID)

AF:

0.0242

AC:

AN:

1734

European-Non Finnish (NFE)

AF:

0.0218

AC:

6065

AN:

278176

Other (OTH)

AF:

0.0221

AC:

507

AN:

22914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

1172

2345

3517

4690

5862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000232

AC:

AN:

137974

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

AN XY:

66874

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000793

AC:

AN:

37836

American (AMR)

AF:

0.0000731

AC:

AN:

13678

Ashkenazi Jewish (ASJ)

AF:

0.000607

AC:

AN:

3294

East Asian (EAS)

AF:

0.00

AC:

AN:

4768

South Asian (SAS)

AF:

0.00

AC:

AN:

4372

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

8074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000238

AC:

AN:

62900

Other (OTH)

AF:

0.00

AC:

AN:

1900

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.039

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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17-28856714-CTTTTTTTT-CTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over