NM_178857.6:c.*226G>C

Variant names:

• chr8-10606669-C-G
• rs12547192
• NM_178857.6:c.*226G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178857.6(RP1L1):​c.*226G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 673,978 control chromosomes in the GnomAD database, including 9,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1680 hom., cov: 34)
  • Exomes 𝑓: 0.16 (8017 hom.)
• Consequence: RP1L1 NM_178857.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.520

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 (BayesDel_noAF=-0.82).
• BP6: Variant 8-10606669-C-G is Benign according to our data. Variant chr8-10606669-C-G is described in ClinVar as [Benign]. Clinvar id is 361196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1L1	NM_178857.6	c.*226G>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000382483.4	NP_849188.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1L1	ENST00000382483	c.*226G>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_178857.6	ENSP00000371923.3

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20031 AN: 152130 Hom.: 1679 Cov.: 34

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.161 AC: 83993 AN: 521730 Hom.: 8017 Cov.: 7 AF XY: 0.170 AC XY: 46112 AN XY: 271058

Gnomad4 AFR exome AF: 0.0547

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.132 AC: 20029 AN: 152248 Hom.: 1680 Cov.: 34 AF XY: 0.140 AC XY: 10435 AN XY: 74452

Gnomad4 AFR AF: 0.0553

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.146

Alfa AF: 0.124 Hom.: 164

Bravo AF: 0.124

Asia WGS AF: 0.255 AC: 887 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Occult macular dystrophy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.39

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: rs12547192; hg19: chr8-10464179;