rs1666946986

Variant names:

• chr1-93353931-T-C
• rs1666946986
• NM_001938.3:c.244T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001938.3(DR1):​c.244T>C​(p.Ser82Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000687 in 1,455,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: DR1 NM_001938.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09
• Publications: 0 publications found

Genes affected

DR1 (HGNC:3017): (down-regulator of transcription 1) This gene encodes a TBP- (TATA box-binding protein) associated phosphoprotein that represses both basal and activated levels of transcription. The encoded protein is phosphorylated in vivo and this phosphorylation affects its interaction with TBP. This protein contains a histone fold motif at the amino terminus, a TBP-binding domain, and a glutamine- and alanine-rich region. The binding of DR1 repressor complexes to TBP-promoter complexes may establish a mechanism in which an altered DNA conformation, together with the formation of higher order complexes, inhibits the assembly of the preinitiation complex and controls the rate of RNA polymerase II transcription. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001938.3. 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
	DR1	NM_001938.3	MANE Select	c.244T>C	p.Ser82Pro	missense	Exon 2 of 3	NP_001929.1	Q01658

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DR1	ENST00000370272.9	TSL:1 MANE Select	c.244T>C	p.Ser82Pro	missense	Exon 2 of 3	ENSP00000359295.3	Q01658
	DR1	ENST00000370267.1	TSL:2	c.244T>C	p.Ser82Pro	missense	Exon 3 of 4	ENSP00000359290.1	Q01658
	DR1	ENST00000937480.1		c.238T>C	p.Ser80Pro	missense	Exon 2 of 3	ENSP00000607539.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455884 Hom.: 0 Cov.: 30 AF XY: 0.00000691 AC XY: 5 AN XY: 724022

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 84534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1109668

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

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	0.24
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Benign	0.15	T
Sift4G	Uncertain	0.025	D
Polyphen		0.97	D
Vest4		0.67
MutPred		0.41		Loss of catalytic residue at S82 (P = 0.0346)
MVP		0.57
MPC		1.5
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.83
gMVP		0.87
Mutation Taster		=17/83	disease causing

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: rs1666946986; hg19: chr1-93819488;