rs4501570

Variant names:

• chr8-63064195-A-G
• rs4501570
• NM_000370.3:c.663+11T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-63064195-A-G
• chr8-63064195-A-T

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+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,586,250 control chromosomes in the GnomAD database, including 203,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28480 hom., cov: 31)
  • Exomes 𝑓: 0.49 (175485 hom.)
• Consequence: TTPA NM_000370.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.677
• Publications: 11 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 8-63064195-A-G is Benign according to our data. Variant chr8-63064195-A-G is described in ClinVar as Benign. ClinVar VariationId is 363558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 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+11T>C		intron	N/A	NP_000361.1	P49638
	TTPA	NM_001413418.1		c.780+11T>C		intron	N/A	NP_001400347.1
	TTPA	NM_001413416.1		c.663+11T>C		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+11T>C		intron	N/A	ENSP00000260116.4	P49638
	TTPA	ENST00000878696.1		c.780+11T>C		intron	N/A	ENSP00000548755.1
	TTPA	ENST00000878697.1		c.552+1709T>C		intron	N/A	ENSP00000548756.1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89798 AN: 151744 Hom.: 28433 Cov.: 31

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.557 AC: 136191 AN: 244296 AF XY: 0.544

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.778

Gnomad FIN exome AF: 0.554

Gnomad NFE exome AF: 0.451

Gnomad OTH exome AF: 0.513

GnomAD4 exome AF: 0.486 AC: 697144 AN: 1434388 Hom.: 175485 Cov.: 27 AF XY: 0.487 AC XY: 348033 AN XY: 714858

African (AFR) AF: 0.826 AC: 27230 AN: 32948

American (AMR) AF: 0.659 AC: 29146 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 11708 AN: 25770

East Asian (EAS) AF: 0.767 AC: 30228 AN: 39424

South Asian (SAS) AF: 0.577 AC: 49237 AN: 85264

European-Finnish (FIN) AF: 0.554 AC: 29360 AN: 53008

Middle Eastern (MID) AF: 0.520 AC: 2978 AN: 5728

European-Non Finnish (NFE) AF: 0.447 AC: 486583 AN: 1088638

Other (OTH) AF: 0.516 AC: 30674 AN: 59392

GnomAD4 genome AF: 0.592 AC: 89901 AN: 151862 Hom.: 28480 Cov.: 31 AF XY: 0.597 AC XY: 44312 AN XY: 74186

African (AFR) AF: 0.817 AC: 33877 AN: 41478

American (AMR) AF: 0.602 AC: 9172 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1621 AN: 3470

East Asian (EAS) AF: 0.775 AC: 4001 AN: 5160

South Asian (SAS) AF: 0.586 AC: 2824 AN: 4818

European-Finnish (FIN) AF: 0.552 AC: 5812 AN: 10524

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

European-Non Finnish (NFE) AF: 0.456 AC: 30973 AN: 67860

Other (OTH) AF: 0.560 AC: 1177 AN: 2100

Alfa AF: 0.515 Hom.: 12287

Bravo AF: 0.604

Asia WGS AF: 0.667 AC: 2314 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial isolated deficiency of vitamin E (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.62
DANN	Benign	0.57
PhyloP100		-0.68
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: rs4501570; hg19: chr8-63976754;