rs4606052

Variant names:

• chr8-63064118-C-T
• rs4606052
• NM_000370.3:c.663+88G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-63064118-C-T
• chr8-63064118-C-G

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.663+88G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 914,400 control chromosomes in the GnomAD database, including 118,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22261 hom., cov: 31)
  • Exomes 𝑓: 0.49 (96063 hom.)
• Consequence: TTPA NM_000370.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.139
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-63064118-C-T is Benign according to our data. Variant chr8-63064118-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 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.663+88G>A		intron	N/A	NP_000361.1	P49638
	TTPA	NM_001413418.1		c.780+88G>A		intron	N/A	NP_001400347.1
	TTPA	NM_001413416.1		c.663+88G>A		intron	N/A	NP_001400345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.663+88G>A		intron	N/A	ENSP00000260116.4	P49638
	TTPA	ENST00000878696.1		c.780+88G>A		intron	N/A	ENSP00000548755.1
	TTPA	ENST00000878697.1		c.552+1786G>A		intron	N/A	ENSP00000548756.1

Frequencies

GnomAD3 genomes AF: 0.534 AC: 80980 AN: 151580 Hom.: 22231 Cov.: 31

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.510

GnomAD4 exome AF: 0.494 AC: 377076 AN: 762702 Hom.: 96063 AF XY: 0.496 AC XY: 197042 AN XY: 397552

African (AFR) AF: 0.613 AC: 11937 AN: 19474

American (AMR) AF: 0.633 AC: 21528 AN: 34028

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 9306 AN: 20730

East Asian (EAS) AF: 0.764 AC: 24976 AN: 32672

South Asian (SAS) AF: 0.570 AC: 36186 AN: 63452

European-Finnish (FIN) AF: 0.554 AC: 25888 AN: 46764

Middle Eastern (MID) AF: 0.504 AC: 2153 AN: 4268

European-Non Finnish (NFE) AF: 0.449 AC: 226459 AN: 504496

Other (OTH) AF: 0.506 AC: 18643 AN: 36818

GnomAD4 genome AF: 0.534 AC: 81057 AN: 151698 Hom.: 22261 Cov.: 31 AF XY: 0.542 AC XY: 40181 AN XY: 74084

African (AFR) AF: 0.618 AC: 25566 AN: 41376

American (AMR) AF: 0.578 AC: 8798 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1607 AN: 3468

East Asian (EAS) AF: 0.774 AC: 4008 AN: 5178

South Asian (SAS) AF: 0.585 AC: 2815 AN: 4808

European-Finnish (FIN) AF: 0.555 AC: 5833 AN: 10504

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30912 AN: 67830

Other (OTH) AF: 0.515 AC: 1084 AN: 2104

Alfa AF: 0.496 Hom.: 2953

Bravo AF: 0.539

Asia WGS AF: 0.652 AC: 2260 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.34
PhyloP100		0.14
Mutation Taster		=10/90	disease causing

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: rs4606052; hg19: chr8-63976677;