20-44480384-T-C

Variant names:

• chr20-44480384-T-C
• NM_001039199.3:c.385T>C

Variant summary

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

The NM_001039199.3(TTPAL):​c.385T>C​(p.Phe129Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTPAL NM_001039199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPAL	NM_001039199.3	c.385T>C	p.Phe129Leu	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.385T>C	p.Phe129Leu	missense_variant	Exon 2 of 5	1	NM_001039199.3	ENSP00000262605.4
TTPAL	ENST00000372904.7	c.385T>C	p.Phe129Leu	missense_variant	Exon 3 of 6	1		ENSP00000361995.3
TTPAL	ENST00000456317.1	c.385T>C	p.Phe129Leu	missense_variant	Exon 2 of 5	2		ENSP00000412720.1
TTPAL	ENST00000372906.2	c.385T>C	p.Phe129Leu	missense_variant	Exon 2 of 3	3		ENSP00000361997.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385T>C (p.F129L) 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 385, causing the phenylalanine (F) at amino acid position 129 to be replaced by a leucine (L). 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	0.98
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.080
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.64	N;N;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.24	B;B;.;.
Vest4		0.91
MutPred		0.53		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.043
MPC		1.2
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.18
gMVP		0.79

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: chr20-43109024;