NM_003322.6:c.200C>G

Variant names:

• chr6-35511797-G-C
• rs7764472
• NM_003322.6:c.200C>G

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.200C>G​(p.Thr67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.853 in 1,557,490 control chromosomes in the GnomAD database, including 568,033 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 Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (59522 hom., cov: 30)
  • Exomes 𝑓: 0.85 (508511 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.430
• Publications: 33 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=6.4844005E-7).
• BP6: Variant 6-35511797-G-C is Benign according to our data. Variant chr6-35511797-G-C is described in ClinVar as Benign. ClinVar VariationId is 286865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.966 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.200C>G	p.Thr67Arg	missense	Exon 4 of 15	NP_003313.3
	TULP1	NM_001289395.2		c.190+383C>G		intron	N/A	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.200C>G	p.Thr67Arg	missense	Exon 4 of 15	ENSP00000229771.6	O00294-1
	TULP1	ENST00000322263.8	TSL:1	c.190+383C>G		intron	N/A	ENSP00000319414.4	O00294-2
	TULP1	ENST00000614066.4	TSL:5	c.200C>G	p.Thr67Arg	missense	Exon 4 of 14	ENSP00000477534.1	A0A087WT25

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134066 AN: 151878 Hom.: 59457 Cov.: 30

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.861

GnomAD2 exomes AF: 0.851 AC: 142773 AN: 167774 AF XY: 0.844

Gnomad AFR exome AF: 0.977

Gnomad AMR exome AF: 0.915

Gnomad ASJ exome AF: 0.807

Gnomad EAS exome AF: 0.843

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.853

Gnomad OTH exome AF: 0.848

GnomAD4 exome AF: 0.850 AC: 1194417 AN: 1405494 Hom.: 508511 Cov.: 64 AF XY: 0.847 AC XY: 587026 AN XY: 693450

African (AFR) AF: 0.977 AC: 31295 AN: 32024

American (AMR) AF: 0.911 AC: 34361 AN: 37710

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 20170 AN: 24908

East Asian (EAS) AF: 0.853 AC: 31212 AN: 36596

South Asian (SAS) AF: 0.779 AC: 62219 AN: 79912

European-Finnish (FIN) AF: 0.817 AC: 39382 AN: 48180

Middle Eastern (MID) AF: 0.790 AC: 4164 AN: 5272

European-Non Finnish (NFE) AF: 0.852 AC: 922331 AN: 1082846

Other (OTH) AF: 0.849 AC: 49283 AN: 58046

GnomAD4 genome AF: 0.883 AC: 134195 AN: 151996 Hom.: 59522 Cov.: 30 AF XY: 0.880 AC XY: 65357 AN XY: 74282

African (AFR) AF: 0.974 AC: 40397 AN: 41484

American (AMR) AF: 0.890 AC: 13621 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2836 AN: 3472

East Asian (EAS) AF: 0.848 AC: 4343 AN: 5120

South Asian (SAS) AF: 0.766 AC: 3691 AN: 4818

European-Finnish (FIN) AF: 0.820 AC: 8668 AN: 10568

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57766 AN: 67920

Other (OTH) AF: 0.860 AC: 1817 AN: 2112

Alfa AF: 0.853 Hom.: 41451

Bravo AF: 0.896

TwinsUK AF: 0.854 AC: 3167

ALSPAC AF: 0.859 AC: 3311

ESP6500AA AF: 0.969 AC: 4097

ESP6500EA AF: 0.864 AC: 7196

ExAC AF: 0.826 AC: 89812

Asia WGS AF: 0.826 AC: 2870 AN: 3476

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	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	0.039
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.5
DANN	Benign	0.19
DEOGEN2	Benign	0.042	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00046	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-0.43
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.18
Sift	Benign	0.90	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.079
MPC		0.30
ClinPred		0.00041	T
GERP RS		0.72
Varity_R		0.039
gMVP		0.16
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs7764472; hg19: chr6-35479574; COSMIC: COSV57692003;