chr20-35004547-G-T

Variant names:

• chr20-35004547-G-T
• rs371612752
• NM_015638.3:c.1960C>A

Variant summary

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

The NM_015638.3(TRPC4AP):​c.1960C>A​(p.Arg654Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,638 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R654C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPC4AP NM_015638.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.76

Genes affected

TRPC4AP (HGNC:16181): (transient receptor potential cation channel subfamily C member 4 associated protein) Enables phosphatase binding activity and ubiquitin ligase-substrate adaptor activity. Involved in protein ubiquitination and ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Part of Cul4A-RING E3 ubiquitin ligase complex. Is active in Cul4-RING E3 ubiquitin ligase complex. [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=0.38837683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC4AP	NM_015638.3	c.1960C>A	p.Arg654Ser	missense_variant	Exon 17 of 19	ENST00000252015.3	NP_056453.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC4AP	ENST00000252015.3	c.1960C>A	p.Arg654Ser	missense_variant	Exon 17 of 19	1	NM_015638.3	ENSP00000252015.2
TRPC4AP	ENST00000451813.6	c.1936C>A	p.Arg646Ser	missense_variant	Exon 17 of 19	2		ENSP00000400614.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249780 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135212

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727082

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.91	.;P
Vest4		0.56
MutPred		0.40		.;Loss of helix (P = 0.0444);
MVP		0.068
MPC		0.41
ClinPred		0.58	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs371612752; hg19: chr20-33592350;