8-10610141-C-CCCCTCTTCTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_StrongBS1_SupportingBS2

The NM_178857.6(RP1L1):c.3956_3957insAAGAAGAGGG(p.Val1320ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0026 ( 5 hom., cov: 19)

Exomes 𝑓: 0.0015 ( 59 hom. )

Failed GnomAD Quality Control

Consequence

RP1L1
NM_178857.6 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.28

Publications

2 publications found

Variant links:

Genes affected

RP1L1 (HGNC:15946): (RP1 like 1) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, and two C-terminal large repetitive regions, both of which contain a high percentage of glutamine and glutamic acid residues. This protein is a retinal-specific protein. Its exact length varies among individuals due to the presence of a 16aa repeat in the first C-terminal repetitive region. The 16aa repeat is encoded by the highly polymorphic 48-bp repeat, and 1-6 copies of the 16aa repeat have been identified in normal individuals. The current reference sequence shown here has a single copy of the 16aa repeat. This protein and the RP1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Mutations in this gene cause occult macular dystrophy (OMD). [provided by RefSeq, Sep 2010]

RP1L1 Gene-Disease associations (from GenCC):

occult macular dystrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
retinitis pigmentosa
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
retinitis pigmentosa 88
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
cone dystrophy
Inheritance: AR Classification: LIMITED Submitted by: G2P

RP1L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00264 (396/149878) while in subpopulation AFR AF = 0.00408 (164/40170). AF 95% confidence interval is 0.00357. There are 5 homozygotes in GnomAd4. There are 201 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1L1	NM_178857.6 link	c.3956_3957insAAGAAGAGGG	p.Val1320ArgfsTer10	frameshift_variant	Exon 4 of 4	ENST00000382483.4	NP_849188.4	Q8IWN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1L1	ENST00000382483.4 link	c.3956_3957insAAGAAGAGGG	p.Val1320ArgfsTer10	frameshift_variant	Exon 4 of 4	1	NM_178857.6	ENSP00000371923.3		Q8IWN7-1

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

396

AN:

149764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00407

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00226

Gnomad ASJ

AF:

0.0117

Gnomad EAS

AF:

0.000791

Gnomad SAS

AF:

0.00147

Gnomad FIN

AF:

0.000578

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00195

Gnomad OTH

AF:

0.00242

GnomAD2 exomes

AF:

0.000501

AC:

122

AN:

243342

AF XY:

0.000568

show subpopulations

Gnomad AFR exome

AF:

0.00214

Gnomad AMR exome

AF:

0.000412

Gnomad ASJ exome

AF:

0.000823

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000945

Gnomad NFE exome

AF:

0.000557

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00146

AC:

1985

AN:

1363938

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1049

AN XY:

677300

show subpopulations

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

African (AFR)

AF:

0.00361

AC:

112

AN:

31006

American (AMR)

AF:

0.00144

AC:

AN:

37436

Ashkenazi Jewish (ASJ)

AF:

0.00820

AC:

195

AN:

23782

East Asian (EAS)

AF:

0.000674

AC:

AN:

29680

South Asian (SAS)

AF:

0.000980

AC:

AN:

79572

European-Finnish (FIN)

AF:

0.00301

AC:

138

AN:

45922

Middle Eastern (MID)

AF:

0.00219

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.00116

AC:

1229

AN:

1055958

Other (OTH)

AF:

0.00267

AC:

147

AN:

55098

⚠️ 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: 0.395

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00264

AC:

396

AN:

149878

Hom.:

Cov.:

AF XY:

0.00274

AC XY:

201

AN XY:

73242

show subpopulations

African (AFR)

AF:

0.00408

AC:

164

AN:

40170

American (AMR)

AF:

0.00225

AC:

AN:

15080

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

AN:

3418

East Asian (EAS)

AF:

0.000595

AC:

AN:

5042

South Asian (SAS)

AF:

0.00147

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.000578

AC:

AN:

10388

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00195

AC:

132

AN:

67720

Other (OTH)

AF:

0.00239

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Occult macular dystrophy;C5394208:Retinitis pigmentosa 88

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-4.3

Mutation Taster

=197/3

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over