NM_178857.6:c.3955G>A

Variant names:

• chr8-10610143-C-T
• rs73201156
• NM_178857.6:c.3955G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:5
• Conservation: PhyloP100: 0.249
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.0030745268).
• BP6: Variant 8-10610143-C-T is Benign according to our data. Variant chr8-10610143-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 361301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1L1	NM_178857.6	MANE Select	c.3955G>A	p.Ala1319Thr	missense	Exon 4 of 4	NP_849188.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1L1	ENST00000382483.4	TSL:1 MANE Select	c.3955G>A	p.Ala1319Thr	missense	Exon 4 of 4	ENSP00000371923.3

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

GnomAD2 exomes AF: 0.0150 AC: 1966 AN: 131088 AF XY: 0.0159

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0120 AC: 290 AN: 24160

American (AMR) AF: 0.00420 AC: 149 AN: 35440

Ashkenazi Jewish (ASJ) AF: 0.00674 AC: 101 AN: 14984

East Asian (EAS) AF: 0.000131 AC: 5 AN: 38216

South Asian (SAS) AF: 0.00909 AC: 596 AN: 65598

European-Finnish (FIN) AF: 0.00443 AC: 156 AN: 35178

Middle Eastern (MID) AF: 0.00677 AC: 22 AN: 3250

European-Non Finnish (NFE) AF: 0.00565 AC: 2774 AN: 491140

Other (OTH) AF: 0.00530 AC: 181 AN: 34172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0104 AC: 272 AN: 26254

American (AMR) AF: 0.00261 AC: 23 AN: 8818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1298

East Asian (EAS) AF: 0.00 AC: 0 AN: 4906

South Asian (SAS) AF: 0.0110 AC: 31 AN: 2814

European-Finnish (FIN) AF: 0.00195 AC: 11 AN: 5638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 118

European-Non Finnish (NFE) AF: 0.00204 AC: 49 AN: 23998

Other (OTH) AF: 0.00203 AC: 2 AN: 984

Alfa AF: 0.0340 Hom.: 3

ExAC AF: 0.0399 AC: 4560

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Occult macular dystrophy (1)
-	-	1	Occult macular dystrophy;C5394208:Retinitis pigmentosa 88 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.25
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
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: rs73201156; hg19: chr8-10467653; COSMIC: COSV66752033;