20-35035236-G-T

Variant names:

• chr20-35035236-G-T
• rs201995082
• NM_015638.3:c.938C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015638.3(TRPC4AP):​c.938C>A​(p.Thr313Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 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. T313M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRPC4AP NM_015638.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.48
• Publications: 0 publications found

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]

TRPC4AP Gene-Disease associations (from GenCC):

• hypothyroidism

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3751005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015638.3. 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
	TRPC4AP	NM_015638.3	MANE Select	c.938C>A	p.Thr313Lys	missense	Exon 8 of 19	NP_056453.1	Q8TEL6-1
	TRPC4AP	NM_199368.2		c.938C>A	p.Thr313Lys	missense	Exon 8 of 19	NP_955400.1	Q8TEL6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC4AP	ENST00000252015.3	TSL:1 MANE Select	c.938C>A	p.Thr313Lys	missense	Exon 8 of 19	ENSP00000252015.2	Q8TEL6-1
	TRPC4AP	ENST00000970992.1		c.938C>A	p.Thr313Lys	missense	Exon 8 of 19	ENSP00000641051.1
	TRPC4AP	ENST00000888656.1		c.938C>A	p.Thr313Lys	missense	Exon 8 of 20	ENSP00000558715.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251328 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Uncertain	0.025	D
Sift4G	Benign	0.62	T
Polyphen		0.83	P
Vest4		0.63
MutPred		0.26		Gain of ubiquitination at T313 (P = 0.0094)
MVP		0.068
MPC		0.37
ClinPred		0.57	D
GERP RS		5.5
Varity_R		0.31
gMVP		0.53
Mutation Taster		=56/44	polymorphism

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: rs201995082; hg19: chr20-33623039;