rs1998233

Variant names:

• chr20-35069323-G-A
• rs1998233
• NM_015638.3:c.387C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000252015.3(TRPC4AP):​c.387C>T​(p.Tyr129Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,602,508 control chromosomes in the GnomAD database, including 427,776 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.77 (45509 hom., cov: 31)
  • Exomes 𝑓: 0.72 (382267 hom.)
• Consequence: TRPC4AP ENST00000252015.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 29 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000252015.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC4AP	NM_015638.3	MANE Select	c.387C>T	p.Tyr129Tyr	synonymous	Exon 3 of 19	NP_056453.1
	TRPC4AP	NM_199368.2		c.387C>T	p.Tyr129Tyr	synonymous	Exon 3 of 19	NP_955400.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC4AP	ENST00000252015.3	TSL:1 MANE Select	c.387C>T	p.Tyr129Tyr	synonymous	Exon 3 of 19	ENSP00000252015.2
	TRPC4AP	ENST00000451813.6	TSL:2	c.387C>T	p.Tyr129Tyr	synonymous	Exon 3 of 19	ENSP00000400614.1

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117104 AN: 151970 Hom.: 45461 Cov.: 31

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.872

Gnomad AMR AF: 0.821

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.783

GnomAD2 exomes AF: 0.769 AC: 192832 AN: 250858 AF XY: 0.763

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.891

Gnomad ASJ exome AF: 0.793

Gnomad EAS exome AF: 0.761

Gnomad FIN exome AF: 0.792

Gnomad NFE exome AF: 0.730

Gnomad OTH exome AF: 0.785

GnomAD4 exome AF: 0.724 AC: 1049727 AN: 1450420 Hom.: 382267 Cov.: 31 AF XY: 0.724 AC XY: 523197 AN XY: 722242

African (AFR) AF: 0.826 AC: 27467 AN: 33266

American (AMR) AF: 0.885 AC: 39529 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 20709 AN: 26060

East Asian (EAS) AF: 0.790 AC: 31258 AN: 39584

South Asian (SAS) AF: 0.722 AC: 62001 AN: 85866

European-Finnish (FIN) AF: 0.792 AC: 42292 AN: 53390

Middle Eastern (MID) AF: 0.870 AC: 4995 AN: 5744

European-Non Finnish (NFE) AF: 0.705 AC: 777357 AN: 1101860

Other (OTH) AF: 0.735 AC: 44119 AN: 60008

GnomAD4 genome AF: 0.771 AC: 117213 AN: 152088 Hom.: 45509 Cov.: 31 AF XY: 0.774 AC XY: 57559 AN XY: 74336

African (AFR) AF: 0.823 AC: 34124 AN: 41484

American (AMR) AF: 0.822 AC: 12554 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2770 AN: 3472

East Asian (EAS) AF: 0.775 AC: 4017 AN: 5180

South Asian (SAS) AF: 0.716 AC: 3450 AN: 4816

European-Finnish (FIN) AF: 0.802 AC: 8486 AN: 10580

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.723 AC: 49112 AN: 67954

Other (OTH) AF: 0.785 AC: 1661 AN: 2116

Alfa AF: 0.741 Hom.: 190487

Bravo AF: 0.780

Asia WGS AF: 0.768 AC: 2671 AN: 3478

EpiCase AF: 0.739

EpiControl AF: 0.745

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.5
DANN	Benign	0.46
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1998233; hg19: chr20-33657126; COSMIC: COSV108042952;