1-95244224-C-T

Variant names:

• chr1-95244224-C-T
• rs202232113
• ENST00000604534.5:c.580C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001199691.1(TLCD4-RWDD3):​c.580C>T​(p.Arg194Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict 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. R194S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: TLCD4-RWDD3 NM_001199691.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.382
• Publications: 0 publications found

Genes affected

TLCD4-RWDD3 (HGNC:49388): (TLCD4-RWDD3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring TMEM56 (transmembrane protein 56) and RWDD3 (RWD domain containing 3) genes on chromosome 1. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product, but it contains a distinct C-terminus due to frameshifts versus the downstream gene coding sequence. [provided by RefSeq, Dec 2010]

RWDD3 (HGNC:21393): (RWD domain containing 3) Involved in negative regulation of NF-kappaB transcription factor activity; positive regulation of hypoxia-inducible factor-1alpha signaling pathway; and positive regulation of protein sumoylation. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000228852 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071231425).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199691.1. 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
	RWDD3	NM_015485.5	MANE Select	c.99C>T	p.Thr33Thr	synonymous	Exon 2 of 4	NP_056300.3	Q9Y3V2-1
	TLCD4-RWDD3	NM_001199691.1		c.580C>T	p.Arg194Cys	missense	Exon 8 of 8	NP_001186620.1	S4R434
	RWDD3	NM_001278248.2		c.54C>T	p.Thr18Thr	synonymous	Exon 3 of 5	NP_001265177.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLCD4-RWDD3	ENST00000604534.5	TSL:2	c.580C>T	p.Arg194Cys	missense	Exon 8 of 8	ENSP00000475025.1	S4R434
	RWDD3	ENST00000370202.5	TSL:3 MANE Select	c.99C>T	p.Thr33Thr	synonymous	Exon 2 of 4	ENSP00000359221.4	Q9Y3V2-1
	RWDD3	ENST00000263893.10	TSL:1	c.99C>T	p.Thr33Thr	synonymous	Exon 2 of 3	ENSP00000263893.6	Q9Y3V2-2

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000168 AC: 42 AN: 249294 AF XY: 0.0000813

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461500 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 36 AN XY: 726974

African (AFR) AF: 0.00233 AC: 78 AN: 33472

American (AMR) AF: 0.000291 AC: 13 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111686

Other (OTH) AF: 0.000132 AC: 8 AN: 60390

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74462

African (AFR) AF: 0.00231 AC: 96 AN: 41548

American (AMR) AF: 0.000719 AC: 11 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000574 Hom.: 0

Bravo AF: 0.000774

ESP6500AA AF: 0.00160 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000190 AC: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	5.2
DANN	Benign	0.70
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0071	T
PhyloP100		-0.38
Vest4		0.093
MVP		0.57
MPC		0.40
GERP RS		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.54
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs202232113; hg19: chr1-95709780;