NM_178857.6:c.3956_3957insAAGAAGAGAG

Variant names:

• chr8-10610141-C-CCTCTCTTCTT
• rs773894295
• NM_178857.6:c.3956_3957insAAGAAGAGAG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PVS1_Strong BP6 BA1

The NM_178857.6(RP1L1):​c.3956_3957insAAGAAGAGAG​(p.Val1320ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.077 (711 hom., cov: 19)
  • Exomes 𝑓: 0.048 (6253 hom.)
  • Failed GnomAD Quality Control
• Consequence: RP1L1 NM_178857.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -4.28
• Publications: 2 publications found

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: Laboratory for Molecular Medicine, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• retinitis pigmentosa 88

  Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• cone dystrophy

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 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.
• BP6: Variant 8-10610141-C-CCTCTCTTCTT is Benign according to our data. Variant chr8-10610141-C-CCTCTCTTCTT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225459.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178857.6. 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
	RP1L1	NM_178857.6	MANE Select	c.3956_3957insAAGAAGAGAG	p.Val1320ArgfsTer10	frameshift	Exon 4 of 4	NP_849188.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1L1	ENST00000382483.4	TSL:1 MANE Select	c.3956_3957insAAGAAGAGAG	p.Val1320ArgfsTer10	frameshift	Exon 4 of 4	ENSP00000371923.3	Q8IWN7-1

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11389 AN: 148502 Hom.: 711 Cov.: 19

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0387

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.0959

Gnomad EAS AF: 0.00891

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0942

Gnomad NFE AF: 0.0728

Gnomad OTH AF: 0.0906

GnomAD2 exomes AF: 0.0406 AC: 9879 AN: 243342 AF XY: 0.0406

Gnomad AFR exome AF: 0.0811

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.0708

Gnomad EAS exome AF: 0.00559

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0503

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0480 AC: 63802 AN: 1328278 Hom.: 6253 Cov.: 38 AF XY: 0.0491 AC XY: 32429 AN XY: 660322

African (AFR) AF: 0.0995 AC: 3051 AN: 30650

American (AMR) AF: 0.0417 AC: 1547 AN: 37104

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 2231 AN: 23480

East Asian (EAS) AF: 0.0331 AC: 983 AN: 29686

South Asian (SAS) AF: 0.0592 AC: 4679 AN: 79098

European-Finnish (FIN) AF: 0.0415 AC: 1895 AN: 45712

Middle Eastern (MID) AF: 0.0783 AC: 420 AN: 5366

European-Non Finnish (NFE) AF: 0.0447 AC: 45701 AN: 1023322

Other (OTH) AF: 0.0612 AC: 3295 AN: 53860

GnomAD4 genome AF: 0.0767 AC: 11397 AN: 148618 Hom.: 711 Cov.: 19 AF XY: 0.0736 AC XY: 5350 AN XY: 72672

African (AFR) AF: 0.109 AC: 4327 AN: 39710

American (AMR) AF: 0.0655 AC: 981 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.0959 AC: 326 AN: 3398

East Asian (EAS) AF: 0.00894 AC: 45 AN: 5036

South Asian (SAS) AF: 0.0614 AC: 292 AN: 4756

European-Finnish (FIN) AF: 0.0281 AC: 291 AN: 10366

Middle Eastern (MID) AF: 0.105 AC: 30 AN: 286

European-Non Finnish (NFE) AF: 0.0728 AC: 4885 AN: 67110

Other (OTH) AF: 0.0895 AC: 185 AN: 2066

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	1	-	Occult macular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.3
Mutation Taster		=197/3	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs773894295; hg19: chr8-10467651;