20-35021259-A-C

Variant names:

• chr20-35021259-A-C
• rs2082881656
• NM_015638.3:c.1149T>G

Variant summary

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

The NM_015638.3(TRPC4AP):​c.1149T>G​(p.His383Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. H383L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPC4AP NM_015638.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0740
• 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 0 ACMG points.

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.1149T>G	p.His383Gln	missense	Exon 9 of 19	NP_056453.1	Q8TEL6-1
	TRPC4AP	NM_199368.2		c.1125T>G	p.His375Gln	missense	Exon 9 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.1149T>G	p.His383Gln	missense	Exon 9 of 19	ENSP00000252015.2	Q8TEL6-1
	TRPC4AP	ENST00000970992.1		c.1149T>G	p.His383Gln	missense	Exon 9 of 19	ENSP00000641051.1
	TRPC4AP	ENST00000888656.1		c.1149T>G	p.His383Gln	missense	Exon 9 of 20	ENSP00000558715.1

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 151366 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000580

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000673

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00708 AC: 9573 AN: 1351366 Hom.: 0 Cov.: 31 AF XY: 0.00654 AC XY: 4418 AN XY: 675772

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00606 AC: 190 AN: 31360

American (AMR) AF: 0.000520 AC: 23 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 72 AN: 25022

East Asian (EAS) AF: 0.00208 AC: 79 AN: 38028

South Asian (SAS) AF: 0.00257 AC: 216 AN: 84134

European-Finnish (FIN) AF: 0.000615 AC: 32 AN: 52002

Middle Eastern (MID) AF: 0.00397 AC: 22 AN: 5536

European-Non Finnish (NFE) AF: 0.00847 AC: 8593 AN: 1014710

Other (OTH) AF: 0.00614 AC: 346 AN: 56356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000139 AC: 21 AN: 151486 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73992

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000482 AC: 2 AN: 41484

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.000580 AC: 2 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.000673 AC: 7 AN: 10398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67696

Other (OTH) AF: 0.00 AC: 0 AN: 2102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.074
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.073	T
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.54		Loss of ubiquitination at K380 (P = 0.0896)
MVP		0.27
MPC		0.94
ClinPred		0.86	D
GERP RS		-3.0
Varity_R		0.18
gMVP		0.56
Mutation Taster		=24/76	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: rs2082881656; hg19: chr20-33609062; COSMIC: COSV108767928;