chr8-63060159-C-T

Variant names:

• chr8-63060159-C-T
• rs4587328
• NM_000370.3:c.*1093G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000370.3(TTPA):​c.*1093G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,090 control chromosomes in the GnomAD database, including 28,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28444 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TTPA NM_000370.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.471
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-63060159-C-T is Benign according to our data. Variant chr8-63060159-C-T is described in ClinVar as Benign. ClinVar VariationId is 363543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

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.*1093G>A		3_prime_UTR	Exon 5 of 5	NP_000361.1	P49638
	TTPA	NM_001413418.1		c.*1093G>A		3_prime_UTR	Exon 6 of 6	NP_001400347.1
	TTPA	NM_001413416.1		c.*1832G>A		3_prime_UTR	Exon 5 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.*1093G>A		3_prime_UTR	Exon 5 of 5	ENSP00000260116.4	P49638
	TTPA	ENST00000878696.1		c.*1093G>A		3_prime_UTR	Exon 6 of 6	ENSP00000548755.1
	TTPA	ENST00000878694.1		c.*1093G>A		3_prime_UTR	Exon 5 of 5	ENSP00000548753.1

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89829 AN: 151974 Hom.: 28398 Cov.: 32

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.554

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.591 AC: 89929 AN: 152090 Hom.: 28444 Cov.: 32 AF XY: 0.597 AC XY: 44360 AN XY: 74354

African (AFR) AF: 0.815 AC: 33839 AN: 41530

American (AMR) AF: 0.602 AC: 9183 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1619 AN: 3468

East Asian (EAS) AF: 0.774 AC: 4014 AN: 5188

South Asian (SAS) AF: 0.585 AC: 2819 AN: 4818

European-Finnish (FIN) AF: 0.553 AC: 5835 AN: 10554

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30994 AN: 67946

Other (OTH) AF: 0.559 AC: 1182 AN: 2114

Alfa AF: 0.438 Hom.: 1440

Bravo AF: 0.603

Asia WGS AF: 0.669 AC: 2323 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial isolated deficiency of vitamin E (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.46
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs4587328; hg19: chr8-63972718;