20-44480411-C-A

Variant names:

• chr20-44480411-C-A
• NM_001039199.3:c.412C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039199.3(TTPAL):​c.412C>A​(p.Pro138Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTPAL NM_001039199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22957578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPAL	NM_001039199.3	c.412C>A	p.Pro138Thr	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.412C>A	p.Pro138Thr	missense_variant	Exon 2 of 5	1	NM_001039199.3	ENSP00000262605.4
TTPAL	ENST00000372904.7	c.412C>A	p.Pro138Thr	missense_variant	Exon 3 of 6	1		ENSP00000361995.3
TTPAL	ENST00000456317.1	c.412C>A	p.Pro138Thr	missense_variant	Exon 2 of 5	2		ENSP00000412720.1
TTPAL	ENST00000372906.2	c.412C>A	p.Pro138Thr	missense_variant	Exon 2 of 3	3		ENSP00000361997.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.412C>A (p.P138T) alteration is located in exon 3 (coding exon 1) of the TTPAL gene. This alteration results from a C to A substitution at nucleotide position 412, causing the proline (P) at amino acid position 138 to be replaced by a threonine (T). 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	Benign	0.075
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.065	T;T;.;.
Eigen	Benign	-0.024
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	0.043	D
MutationAssessor	Benign	1.4	L;L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.80	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.023	B;B;.;.
Vest4		0.21
MutPred		0.44		Gain of catalytic residue at P138 (P = 0.0466);Gain of catalytic residue at P138 (P = 0.0466);Gain of catalytic residue at P138 (P = 0.0466);Gain of catalytic residue at P138 (P = 0.0466);
MVP		0.043
MPC		0.48
ClinPred		0.57	D
GERP RS		4.9
Varity_R		0.12
gMVP		0.72

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43109051;