chr8-10606629-G-A

Variant names:

• chr8-10606629-G-A
• rs557198895
• NM_178857.6:c.*266C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_178857.6(RP1L1):​c.*266C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000673 in 521,512 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: RP1L1 NM_178857.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.633
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-10606629-G-A is Benign according to our data. Variant chr8-10606629-G-A is described in ClinVar as Benign. ClinVar VariationId is 361193.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00178 (271/152332) while in subpopulation AFR AF = 0.0062 (258/41580). AF 95% confidence interval is 0.00558. There are 2 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD gene

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.*266C>T		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.*266C>T		3_prime_UTR	Exon 4 of 4	ENSP00000371923.3	Q8IWN7-1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152214 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000217 AC: 80 AN: 369180 Hom.: 0 Cov.: 4 AF XY: 0.000186 AC XY: 36 AN XY: 193926

African (AFR) AF: 0.00561 AC: 60 AN: 10686

American (AMR) AF: 0.000537 AC: 7 AN: 13036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11320

East Asian (EAS) AF: 0.00 AC: 0 AN: 23094

South Asian (SAS) AF: 0.0000254 AC: 1 AN: 39362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1608

European-Non Finnish (NFE) AF: 0.0000264 AC: 6 AN: 227454

Other (OTH) AF: 0.000285 AC: 6 AN: 21068

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152332 Hom.: 2 Cov.: 34 AF XY: 0.00160 AC XY: 119 AN XY: 74490

African (AFR) AF: 0.00620 AC: 258 AN: 41580

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Occult macular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.64
DANN	Benign	0.69
PhyloP100		-0.63

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: rs557198895; hg19: chr8-10464139; COSMIC: COSV105321601;