rs2064317

Variant names:

• chr6-35509255-A-G
• rs2064317
• NM_003322.6:c.776T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_003322.6(TULP1):​c.776T>C​(p.Ile259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,612,918 control chromosomes in the GnomAD database, including 119,560 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10494 hom., cov: 31)
  • Exomes 𝑓: 0.38 (109066 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.854
• Publications: 35 publications found

Genes affected

TULP1 (HGNC:12423): (TUB like protein 1) This gene encodes a member of the tubby-like gene family (TULPs). Members of this family have been identified in plants, vertebrates, and invertebrates. TULP proteins share a conserved C-terminal region of approximately 200 amino acid residues. The protein encoded by this gene is thought to play a role in the physiology of photoreceptors. Mutations in this gene are associated with recessive juvenile retinitis pigmentosa and Leber congenital amaurosis-15. [provided by RefSeq, Nov 2016]

TULP1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis 15

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LINC03135 (HGNC:58100):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.64726 (below the threshold of 3.09). Trascript score misZ: -0.4024 (below the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa, retinitis pigmentosa 14, Leber congenital amaurosis, Leber congenital amaurosis 15.
• BP4: Computational evidence support a benign effect (MetaRNN=6.7973137E-4).
• BP6: Variant 6-35509255-A-G is Benign according to our data. Variant chr6-35509255-A-G is described in ClinVar as Benign. ClinVar VariationId is 99671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003322.6. 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
	TULP1	NM_003322.6	MANE Select	c.776T>C	p.Ile259Thr	missense	Exon 8 of 15	NP_003313.3
	TULP1	NM_001289395.2		c.617T>C	p.Ile206Thr	missense	Exon 7 of 14	NP_001276324.1	O00294-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TULP1	ENST00000229771.11	TSL:1 MANE Select	c.776T>C	p.Ile259Thr	missense	Exon 8 of 15	ENSP00000229771.6	O00294-1
	TULP1	ENST00000322263.8	TSL:1	c.617T>C	p.Ile206Thr	missense	Exon 7 of 14	ENSP00000319414.4	O00294-2
	TULP1	ENST00000614066.4	TSL:5	c.776T>C	p.Ile259Thr	missense	Exon 8 of 14	ENSP00000477534.1	A0A087WT25

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55979 AN: 151560 Hom.: 10488 Cov.: 31

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.381 AC: 95819 AN: 251456 AF XY: 0.380

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.493

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.376

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.384 AC: 560422 AN: 1461240 Hom.: 109066 Cov.: 60 AF XY: 0.382 AC XY: 278027 AN XY: 726976

African (AFR) AF: 0.347 AC: 11608 AN: 33472

American (AMR) AF: 0.359 AC: 16064 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6651 AN: 26128

East Asian (EAS) AF: 0.434 AC: 17236 AN: 39698

South Asian (SAS) AF: 0.418 AC: 36052 AN: 86244

European-Finnish (FIN) AF: 0.388 AC: 20726 AN: 53396

Middle Eastern (MID) AF: 0.209 AC: 1205 AN: 5766

European-Non Finnish (NFE) AF: 0.385 AC: 427851 AN: 1111432

Other (OTH) AF: 0.381 AC: 23029 AN: 60380

GnomAD4 genome AF: 0.369 AC: 56013 AN: 151678 Hom.: 10494 Cov.: 31 AF XY: 0.372 AC XY: 27569 AN XY: 74094

African (AFR) AF: 0.346 AC: 14306 AN: 41318

American (AMR) AF: 0.353 AC: 5382 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2548 AN: 5104

South Asian (SAS) AF: 0.434 AC: 2090 AN: 4812

European-Finnish (FIN) AF: 0.384 AC: 4038 AN: 10514

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.379 AC: 25733 AN: 67900

Other (OTH) AF: 0.316 AC: 667 AN: 2108

Alfa AF: 0.373 Hom.: 23777

Bravo AF: 0.362

TwinsUK AF: 0.383 AC: 1420

ALSPAC AF: 0.385 AC: 1484

ESP6500AA AF: 0.355 AC: 1564

ESP6500EA AF: 0.371 AC: 3190

ExAC AF: 0.384 AC: 46659

Asia WGS AF: 0.429 AC: 1494 AN: 3478

EpiCase AF: 0.351

EpiControl AF: 0.344

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	Leber congenital amaurosis 15 (2)
-	-	1	Leber congenital amaurosis 1 (1)
-	-	1	not specified (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.1
DANN	Benign	0.13
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.00068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.85
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	0.58	T
Polyphen		0.0010	B
Vest4		0.10
MPC		0.33
ClinPred		0.0036	T
GERP RS		3.6
Varity_R		0.037
gMVP		0.031
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2064317; hg19: chr6-35477032; COSMIC: COSV57692162; COSMIC: COSV57692162;