chr20-44480183-C-T

Variant names:

• chr20-44480183-C-T
• rs2122784099
• NM_001039199.3:c.184C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001039199.3(TTPAL):​c.184C>T​(p.Arg62Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,840 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTPAL NM_001039199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039199.3. 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
	TTPAL	NM_001039199.3	MANE Select	c.184C>T	p.Arg62Cys	missense	Exon 2 of 5	NP_001034288.1	Q9BTX7
	TTPAL	NM_024331.5		c.184C>T	p.Arg62Cys	missense	Exon 3 of 6	NP_077307.2	Q9BTX7
	TTPAL	NM_001261839.2		c.184C>T	p.Arg62Cys	missense	Exon 2 of 5	NP_001248768.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPAL	ENST00000262605.9	TSL:1 MANE Select	c.184C>T	p.Arg62Cys	missense	Exon 2 of 5	ENSP00000262605.4	Q9BTX7
	TTPAL	ENST00000372904.7	TSL:1	c.184C>T	p.Arg62Cys	missense	Exon 3 of 6	ENSP00000361995.3	Q9BTX7
	TTPAL	ENST00000901707.1		c.184C>T	p.Arg62Cys	missense	Exon 2 of 5	ENSP00000571766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		1.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.74		Loss of MoRF binding (P = 0.0148)
MVP		0.28
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.87
Mutation Taster		=31/69	disease causing

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: rs2122784099; hg19: chr20-43108823; COSMIC: COSV52828237;