rs397515523

Variant names:

• chr8-63085831-T-C
• rs397515523
• NM_000370.3:c.191A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000370.3(TTPA):​c.191A>G​(p.Asp64Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,246 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D64E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TTPA NM_000370.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.40
• Publications: 4 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000370.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	NM_000370.3	MANE Select	c.191A>G	p.Asp64Gly	missense	Exon 1 of 5	NP_000361.1
	TTPA	NM_001413418.1		c.191A>G	p.Asp64Gly	missense	Exon 1 of 6	NP_001400347.1
	TTPA	NM_001413416.1		c.191A>G	p.Asp64Gly	missense	Exon 1 of 5	NP_001400345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.191A>G	p.Asp64Gly	missense	Exon 1 of 5	ENSP00000260116.4
	TTPA	ENST00000521138.1	TSL:5	n.219A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384246 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31068

American (AMR) AF: 0.00 AC: 0 AN: 35558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25082

East Asian (EAS) AF: 0.00 AC: 0 AN: 35530

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4464

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077496

Other (OTH) AF: 0.00 AC: 0 AN: 57636

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00166 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Familial isolated deficiency of vitamin E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.14	T
Polyphen		0.0070	B
Vest4		0.75
MutPred		0.84		Gain of MoRF binding (P = 0.0689)
MVP		0.81
MPC		0.24
ClinPred		0.75	D
GERP RS		3.1
PromoterAI		0.25	Neutral
Varity_R		0.73
gMVP		0.58
Mutation Taster		=17/83	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: rs397515523; hg19: chr8-63998390; COSMIC: COSV52646269;