rs73201156

chr8-10610143-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178857.6(RP1L1):c.3955G>A(p.Ala1319Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 817,348 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1319G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 20)
  • Exomes 𝑓: 0.0058 (107 hom.)
• Consequence: RP1L1 NM_178857.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.249

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030745268).
• BP6: Variant 8-10610143-C-T is Benign according to our data. Variant chr8-10610143-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 361301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-10610143-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00516 (388/75210) while in subpopulation SAS AF= 0.011 (31/2814). AF 95% confidence interval is 0.00935. There are 5 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP1L1	NM_178857.6	c.3955G>A	p.Ala1319Thr	missense_variant	4/4	ENST00000382483.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP1L1	ENST00000382483.4	c.3955G>A	p.Ala1319Thr	missense_variant	4/4	1	NM_178857.6	P1

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 390 AN: 75110 Hom.: 5 Cov.: 20

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00261

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00208

GnomAD3 exomes AF: 0.0150 AC: 1966 AN: 131088 Hom.: 67 AF XY: 0.0159 AC XY: 1113 AN XY: 69934

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.000460

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00576 AC: 4274 AN: 742138 Hom.: 107 Cov.: 90 AF XY: 0.00584 AC XY: 2202 AN XY: 377036

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00674

Gnomad4 EAS exome AF: 0.000131

Gnomad4 SAS exome AF: 0.00909

Gnomad4 FIN exome AF: 0.00443

Gnomad4 NFE exome AF: 0.00565

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00516 AC: 388 AN: 75210 Hom.: 5 Cov.: 20 AF XY: 0.00565 AC XY: 215 AN XY: 38086

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00195

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00203

Alfa AF: 0.0541 Hom.: 3

ExAC AF: 0.0399 AC: 4560

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (fails quality filter) -

Occult macular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Occult macular dystrophy;C5394208:Retinitis pigmentosa 88 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	8.4
Dann	Benign	0.29
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.014
Sift	Benign	0.48	T
Sift4G	Benign	0.58	T
Vest4		0.026
ClinPred		0.00037	T
GERP RS		0.064
Varity_R		0.028
gMVP		0.050

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

LitVar

Other links and lift over

dbSNP: rs73201156; hg19: chr8-10467653; COSMIC: COSV66752033;