20-44480156-T-C

Variant names:

• chr20-44480156-T-C
• NM_001039199.3:c.157T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001039199.3(TTPAL):​c.157T>C​(p.Trp53Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTPAL NM_001039199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

Genes affected

TTPAL (HGNC:16114): (alpha tocopherol transfer protein like) Predicted to enable phosphatidylinositol bisphosphate binding activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2652644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPAL	NM_001039199.3	c.157T>C	p.Trp53Arg	missense_variant	Exon 2 of 5	ENST00000262605.9	NP_001034288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPAL	ENST00000262605.9	c.157T>C	p.Trp53Arg	missense_variant	Exon 2 of 5	1	NM_001039199.3	ENSP00000262605.4
TTPAL	ENST00000372904.7	c.157T>C	p.Trp53Arg	missense_variant	Exon 3 of 6	1		ENSP00000361995.3
TTPAL	ENST00000456317.1	c.157T>C	p.Trp53Arg	missense_variant	Exon 2 of 5	2		ENSP00000412720.1
TTPAL	ENST00000372906.2	c.157T>C	p.Trp53Arg	missense_variant	Exon 2 of 3	3		ENSP00000361997.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157T>C (p.W53R) alteration is located in exon 3 (coding exon 1) of the TTPAL gene. This alteration results from a T to C substitution at nucleotide position 157, causing the tryptophan (W) at amino acid position 53 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.019	T;T;.;.
Eigen	Benign	0.069
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	.;D;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-2.5	N;N;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.95	P;P;.;.
Vest4		0.77
MutPred		0.36		Gain of disorder (P = 5e-04);Gain of disorder (P = 5e-04);Gain of disorder (P = 5e-04);Gain of disorder (P = 5e-04);
MVP		0.082
MPC		1.6
ClinPred		0.77	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.33
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43108796;