NM_003322.6:c.1486G>A

Variant names:

• chr6-35499990-C-T
• rs141980901
• NM_003322.6:c.1486G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_003322.6(TULP1):​c.1486G>A​(p.Ala496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,614,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A496V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6 O:1
• Conservation: PhyloP100: -0.0830
• Publications: 7 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):

LOC124901309 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003322.6
• 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=0.00881651).
• BP6: Variant 6-35499990-C-T is Benign according to our data. Variant chr6-35499990-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99664.

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.1486G>A	p.Ala496Thr	missense	Exon 14 of 15	NP_003313.3
	TULP1	NM_001289395.2		c.1327G>A	p.Ala443Thr	missense	Exon 13 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.1486G>A	p.Ala496Thr	missense	Exon 14 of 15	ENSP00000229771.6	O00294-1
	TULP1	ENST00000322263.8	TSL:1	c.1327G>A	p.Ala443Thr	missense	Exon 13 of 14	ENSP00000319414.4	O00294-2
	TULP1	ENST00000614066.4	TSL:5	c.1480G>A	p.Ala494Thr	missense	Exon 13 of 14	ENSP00000477534.1	A0A087WT25

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000860 AC: 216 AN: 251230 AF XY: 0.000861

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000674 AC: 985 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.000649 AC XY: 472 AN XY: 727204

African (AFR) AF: 0.00176 AC: 59 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53306

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.000560 AC: 623 AN: 1112004

Other (OTH) AF: 0.00177 AC: 107 AN: 60396

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74450

African (AFR) AF: 0.00111 AC: 46 AN: 41552

American (AMR) AF: 0.00405 AC: 62 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68002

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (5)
-	-	2	not specified (2)
-	1	-	Leber congenital amaurosis 15 (1)
-	1	-	Retinitis pigmentosa (1)
-	-	1	TULP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.083
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.16
Sift	Benign	0.37	T
Sift4G	Benign	0.53	T
Polyphen		0.73	P
Vest4		0.36
MVP		0.49
MPC		0.57
ClinPred		0.013	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.18
Mutation Taster		=94/6	polymorphism

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: rs141980901; hg19: chr6-35467767;