8-10606560-A-C

Variant names:

• chr8-10606560-A-C
• rs58309857
• NM_178857.6:c.*335T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178857.6(RP1L1):​c.*335T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 318,570 control chromosomes in the GnomAD database, including 4,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2046 hom., cov: 34)
  • Exomes 𝑓: 0.13 (2031 hom.)
• Consequence: RP1L1 NM_178857.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.669
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-10606560-A-C is Benign according to our data. Variant chr8-10606560-A-C is described in ClinVar as Benign. ClinVar VariationId is 361190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.403 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.*335T>G		3_prime_UTR	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.*335T>G		3_prime_UTR	Exon 4 of 4	ENSP00000371923.3	Q8IWN7-1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22882 AN: 152110 Hom.: 2036 Cov.: 34

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.135 AC: 22429 AN: 166342 Hom.: 2031 Cov.: 2 AF XY: 0.134 AC XY: 11703 AN XY: 87552

African (AFR) AF: 0.169 AC: 782 AN: 4616

American (AMR) AF: 0.146 AC: 833 AN: 5724

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 529 AN: 4986

East Asian (EAS) AF: 0.398 AC: 3277 AN: 8236

South Asian (SAS) AF: 0.110 AC: 2326 AN: 21094

European-Finnish (FIN) AF: 0.0677 AC: 554 AN: 8182

Middle Eastern (MID) AF: 0.135 AC: 93 AN: 688

European-Non Finnish (NFE) AF: 0.124 AC: 12806 AN: 103620

Other (OTH) AF: 0.134 AC: 1229 AN: 9196

GnomAD4 genome AF: 0.151 AC: 22923 AN: 152228 Hom.: 2046 Cov.: 34 AF XY: 0.148 AC XY: 11009 AN XY: 74446

African (AFR) AF: 0.172 AC: 7158 AN: 41530

American (AMR) AF: 0.171 AC: 2610 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 419 AN: 3472

East Asian (EAS) AF: 0.418 AC: 2151 AN: 5150

South Asian (SAS) AF: 0.114 AC: 551 AN: 4828

European-Finnish (FIN) AF: 0.0659 AC: 700 AN: 10618

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8837 AN: 68012

Other (OTH) AF: 0.158 AC: 334 AN: 2112

Alfa AF: 0.136 Hom.: 301

Bravo AF: 0.160

Asia WGS AF: 0.275 AC: 954 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.6
DANN	Benign	0.68
PhyloP100		0.67
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: rs58309857; hg19: chr8-10464070;