6-35509248-C-G

Variant names:

• chr6-35509248-C-G
• rs2064318
• NM_003322.6:c.783G>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.783G>C​(p.Lys261Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,613,322 control chromosomes in the GnomAD database, including 543,689 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.84 (53955 hom., cov: 31)
  • Exomes 𝑓: 0.82 (489734 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.903
• 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 15, Leber congenital amaurosis.
• BP4: Computational evidence support a benign effect (MetaRNN=6.118131E-7).
• BP6: Variant 6-35509248-C-G is Benign according to our data. Variant chr6-35509248-C-G is described in ClinVar as Benign. ClinVar VariationId is 94127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.894 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.783G>C	p.Lys261Asn	missense	Exon 8 of 15	NP_003313.3
	TULP1	NM_001289395.2		c.624G>C	p.Lys208Asn	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.783G>C	p.Lys261Asn	missense	Exon 8 of 15	ENSP00000229771.6	O00294-1
	TULP1	ENST00000322263.8	TSL:1	c.624G>C	p.Lys208Asn	missense	Exon 7 of 14	ENSP00000319414.4	O00294-2
	TULP1	ENST00000614066.4	TSL:5	c.783G>C	p.Lys261Asn	missense	Exon 8 of 14	ENSP00000477534.1	A0A087WT25

Frequencies

GnomAD3 genomes AF: 0.842 AC: 127804 AN: 151838 Hom.: 53898 Cov.: 31

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.810

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.827

GnomAD2 exomes AF: 0.823 AC: 206899 AN: 251466 AF XY: 0.815

Gnomad AFR exome AF: 0.901

Gnomad AMR exome AF: 0.900

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.840

Gnomad FIN exome AF: 0.781

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.820

GnomAD4 exome AF: 0.818 AC: 1195242 AN: 1461366 Hom.: 489734 Cov.: 64 AF XY: 0.815 AC XY: 592219 AN XY: 727036

African (AFR) AF: 0.904 AC: 30260 AN: 33472

American (AMR) AF: 0.895 AC: 40032 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 20961 AN: 26132

East Asian (EAS) AF: 0.850 AC: 33730 AN: 39698

South Asian (SAS) AF: 0.758 AC: 65349 AN: 86246

European-Finnish (FIN) AF: 0.784 AC: 41839 AN: 53392

Middle Eastern (MID) AF: 0.773 AC: 4459 AN: 5768

European-Non Finnish (NFE) AF: 0.818 AC: 909114 AN: 1111556

Other (OTH) AF: 0.820 AC: 49498 AN: 60378

GnomAD4 genome AF: 0.842 AC: 127925 AN: 151956 Hom.: 53955 Cov.: 31 AF XY: 0.840 AC XY: 62355 AN XY: 74256

African (AFR) AF: 0.901 AC: 37372 AN: 41460

American (AMR) AF: 0.860 AC: 13142 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 2810 AN: 3468

East Asian (EAS) AF: 0.844 AC: 4324 AN: 5124

South Asian (SAS) AF: 0.747 AC: 3604 AN: 4822

European-Finnish (FIN) AF: 0.787 AC: 8293 AN: 10540

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55582 AN: 67948

Other (OTH) AF: 0.827 AC: 1747 AN: 2112

Alfa AF: 0.821 Hom.: 38368

Bravo AF: 0.853

TwinsUK AF: 0.818 AC: 3034

ALSPAC AF: 0.826 AC: 3182

ESP6500AA AF: 0.890 AC: 3921

ESP6500EA AF: 0.818 AC: 7033

ExAC AF: 0.821 AC: 99730

Asia WGS AF: 0.809 AC: 2812 AN: 3478

EpiCase AF: 0.814

EpiControl AF: 0.806

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Leber congenital amaurosis 15 (2)
-	-	1	Leber congenital amaurosis 1 (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	0.033
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.098
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	6.1e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.90
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.071		Loss of methylation at K261 (P = 0.0032)
MPC		0.31
ClinPred		0.0049	T
GERP RS		3.7
Varity_R		0.068
gMVP		0.044
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2064318; hg19: chr6-35477025; COSMIC: COSV100004002; COSMIC: COSV100004002;