8-10622867-G-C

Variant names:

• chr8-10622867-G-C
• rs6601495
• NM_178857.6:c.335C>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.335C>G​(p.Thr112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0363 in 1,613,054 control chromosomes in the GnomAD database, including 17,275 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T112I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (9086 hom., cov: 31)
  • Exomes 𝑓: 0.020 (8189 hom.)
• Consequence: RP1L1 NM_178857.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.60
• Publications: 9 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Laboratory for Molecular Medicine
• retinitis pigmentosa

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

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=9.029263E-6).
• BP6: Variant 8-10622867-G-C is Benign according to our data. Variant chr8-10622867-G-C is described in ClinVar as Benign. ClinVar VariationId is 361416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.646 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.335C>G	p.Thr112Ser	missense	Exon 2 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.335C>G	p.Thr112Ser	missense	Exon 2 of 4	ENSP00000371923.3	Q8IWN7-1
	RP1L1	ENST00000329335.3	TSL:2	n.585C>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28692 AN: 151924 Hom.: 9051 Cov.: 31

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.0477 AC: 11668 AN: 244860 AF XY: 0.0361

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0204 AC: 29849 AN: 1461012 Hom.: 8189 Cov.: 32 AF XY: 0.0176 AC XY: 12809 AN XY: 726720

African (AFR) AF: 0.678 AC: 22667 AN: 33450

American (AMR) AF: 0.0401 AC: 1792 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 400 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00228 AC: 197 AN: 86234

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53290

Middle Eastern (MID) AF: 0.0366 AC: 211 AN: 5762

European-Non Finnish (NFE) AF: 0.00165 AC: 1836 AN: 1111458

Other (OTH) AF: 0.0455 AC: 2744 AN: 60342

GnomAD4 genome AF: 0.189 AC: 28780 AN: 152042 Hom.: 9086 Cov.: 31 AF XY: 0.184 AC XY: 13674 AN XY: 74320

African (AFR) AF: 0.653 AC: 27017 AN: 41374

American (AMR) AF: 0.0797 AC: 1219 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.00271 AC: 184 AN: 68014

Other (OTH) AF: 0.132 AC: 279 AN: 2110

Alfa AF: 0.0306 Hom.: 920

Bravo AF: 0.217

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.572 AC: 2202

ESP6500EA AF: 0.00412 AC: 34

ExAC AF: 0.0575 AC: 6934

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00374

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Occult macular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.090
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0000090	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Benign	0.079	T
Sift4G	Uncertain	0.027	D
Vest4		0.37
MutPred		0.29		Gain of glycosylation at P113 (P = 0.097)
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.067
gMVP		0.15
Mutation Taster		=88/12	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: rs6601495; hg19: chr8-10480377; COSMIC: COSV61444467;