rs371612752

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-35004547-G-A
• chr20-35004547-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015638.3(TRPC4AP):​c.1960C>T​(p.Arg654Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R654H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: TRPC4AP NM_015638.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23843563).
• BS2: High AC in GnomAd4 at 6 AD gene.

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.1960C>T	p.Arg654Cys	missense	Exon 17 of 19	NP_056453.1	Q8TEL6-1
	TRPC4AP	NM_199368.2		c.1936C>T	p.Arg646Cys	missense	Exon 17 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.1960C>T	p.Arg654Cys	missense	Exon 17 of 19	ENSP00000252015.2	Q8TEL6-1
	TRPC4AP	ENST00000970992.1		c.2254C>T	p.Arg752Cys	missense	Exon 17 of 19	ENSP00000641051.1
	TRPC4AP	ENST00000888656.1		c.1960C>T	p.Arg654Cys	missense	Exon 17 of 20	ENSP00000558715.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249780 AF XY: 0.0000222

Gnomad AFR exome AF: 0.0000620

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727082

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

American (AMR) AF: 0.00 AC: 0 AN: 44704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

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

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.074
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.066	B
Vest4		0.47
MVP		0.043
MPC		0.47
ClinPred		0.18	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.50
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs371612752; hg19: chr20-33592350; COSMIC: COSV52680504; COSMIC: COSV52680504;