21-36073015-G-T

Variant names:

• chr21-36073015-G-T
• rs9024
• NM_001757.4:c.*133G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001757.4(CBR1):​c.*133G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 445,460 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CBR1 NM_001757.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.79
• Publications: 0 publications found

Genes affected

CBR1 (HGNC:1548): (carbonyl reductase 1) The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2013]

SETD4 (HGNC:1258): (SET domain containing 4) Enables histone methyltransferase activity (H4-K20 specific). Involved in histone H4-K20 trimethylation. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CBR1-AS1 (HGNC:55777): (CBR1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001757.4. 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
	CBR1	NM_001757.4	MANE Select	c.*133G>T		3_prime_UTR	Exon 3 of 3	NP_001748.1	P16152-1
	CBR1	NM_001286789.2		c.*1076G>T		3_prime_UTR	Exon 3 of 3	NP_001273718.1	P16152-2
	CBR1-AS1	NR_040084.1		n.377+1866C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBR1	ENST00000290349.11	TSL:1 MANE Select	c.*133G>T		3_prime_UTR	Exon 3 of 3	ENSP00000290349.6	P16152-1
	CBR1	ENST00000530908.5	TSL:1	c.*1076G>T		3_prime_UTR	Exon 3 of 3	ENSP00000434613.1	P16152-2
	SETD4	ENST00000399201.5	TSL:1	c.-203+6290C>A		intron	N/A	ENSP00000382152.1	A8MTS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000224 AC: 1 AN: 445460 Hom.: 0 Cov.: 6 AF XY: 0.00000433 AC XY: 1 AN XY: 231022

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

African (AFR) AF: 0.00 AC: 0 AN: 12176

American (AMR) AF: 0.00 AC: 0 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12924

East Asian (EAS) AF: 0.00 AC: 0 AN: 29634

South Asian (SAS) AF: 0.00 AC: 0 AN: 34306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1922

European-Non Finnish (NFE) AF: 0.00000349 AC: 1 AN: 286256

Other (OTH) AF: 0.00 AC: 0 AN: 25366

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.042
DANN	Benign	0.51
PhyloP100		-2.8

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: rs9024; hg19: chr21-37445313;