8-63086020-A-G

Variant names:

• chr8-63086020-A-G
• rs786204758
• NM_000370.3:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000370.3(TTPA):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,428,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TTPA NM_000370.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.00800
• Publications: 9 publications found

Genes affected

TTPA (HGNC:12404): (alpha tocopherol transfer protein) This gene encodes a soluble protein that binds alpha-trocopherol, a form of vitamin E, with high selectivity and affinity. This protein plays an important role in regulating vitamin E levels in the body by transporting vitamin E between membrane vesicles and facilitating the secretion of vitamin E from hepatocytes to circulating lipoproteins. Mutations in this gene cause hereditary vitamin E deficiency (ataxia with vitamin E deficiency, AVED) and retinitis pigmentosa. [provided by RefSeq, Nov 2009]

TTPA Gene-Disease associations (from GenCC):

• familial isolated deficiency of vitamin E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 65 pathogenic variants. Next in-frame start position is after 209 codons. Genomic position: 63064244. Lost 0.747 part of the original CDS.
• PS1: Another start lost variant in NM_000370.3 (TTPA) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-63086020-A-G is Pathogenic according to our data. Variant chr8-63086020-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000370.3. 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
	TTPA	NM_000370.3	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	NP_000361.1
	TTPA	NM_001413418.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 6	NP_001400347.1
	TTPA	NM_001413416.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 5	NP_001400345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	ENSP00000260116.4
	TTPA	ENST00000878696.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 6	ENSP00000548755.1
	TTPA	ENST00000878697.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 4	ENSP00000548756.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151910 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.0000133 AC: 17 AN: 1276686 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 9 AN XY: 628708

African (AFR) AF: 0.00 AC: 0 AN: 26012

American (AMR) AF: 0.0000865 AC: 2 AN: 23112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21604

East Asian (EAS) AF: 0.00 AC: 0 AN: 27494

South Asian (SAS) AF: 0.00 AC: 0 AN: 65204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3672

European-Non Finnish (NFE) AF: 0.00000975 AC: 10 AN: 1025536

Other (OTH) AF: 0.0000961 AC: 5 AN: 52050

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151910 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74214

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67944

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Familial isolated deficiency of vitamin E (2)
1	-	-	TTPA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.86	T
PhyloP100		-0.0080
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.044	D
Polyphen		0.020	B
Vest4		0.83
MutPred		0.99		Gain of glycosylation at M1 (P = 0.0067)
MVP		0.66
ClinPred		0.99	D
GERP RS		-0.16
PromoterAI		-0.071	Neutral
Varity_R		0.61
gMVP		0.60
Mutation Taster		=48/152	disease causing (ClinVar)

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: rs786204758; hg19: chr8-63998579;