rs374119905

Variant names:

• chr16-90040515-C-T
• rs374119905
• NM_001481.3:c.1221+6C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001481.3(DRC4):​c.1221+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,591,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: DRC4 NM_001481.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005388
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.921
• Publications: 0 publications found

Genes affected

DRC4 (HGNC:4166): (growth arrest specific 8) This gene includes 11 exons spanning 25 kb and maps to a region of chromosome 16 that is sometimes deleted in breast and prostrate cancer. The second intron contains an apparently intronless gene, C16orf3, that is transcribed in the opposite orientation. This gene is a putative tumor suppressor gene. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

URAHP (HGNC:):

URAHP (HGNC:43695): (urate (hydroxyiso-) hydrolase, pseudogene) Predicted to enable hydroxyisourate hydrolase activity. Predicted to be involved in allantoin metabolic process; purine-containing compound catabolic process; and urate catabolic process. Predicted to be active in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000174 (251/1439706) while in subpopulation MID AF = 0.00164 (7/4260). AF 95% confidence interval is 0.000771. There are 1 homozygotes in GnomAdExome4. There are 119 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001481.3. 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
	DRC4	NM_001481.3	MANE Select	c.1221+6C>T		splice_region intron	N/A	NP_001472.1	O95995-1
	DRC4	NM_001286209.2		c.1146+6C>T		splice_region intron	N/A	NP_001273138.1	O95995-2
	DRC4	NM_001286205.2		c.972+6C>T		splice_region intron	N/A	NP_001273134.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAS8	ENST00000268699.9	TSL:1 MANE Select	c.1221+6C>T		splice_region intron	N/A	ENSP00000268699.4	O95995-1
	URAHP	ENST00000409873.5	TSL:1	n.693-98G>A		intron	N/A
	GAS8	ENST00000566266.5	TSL:1	n.*1181+6C>T		splice_region intron	N/A	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000162

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000217 AC: 46 AN: 212388 AF XY: 0.000209

Gnomad AFR exome AF: 0.0000776

Gnomad AMR exome AF: 0.000421

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000746

GnomAD4 exome AF: 0.000174 AC: 251 AN: 1439706 Hom.: 1 Cov.: 32 AF XY: 0.000167 AC XY: 119 AN XY: 714440

African (AFR) AF: 0.0000913 AC: 3 AN: 32876

American (AMR) AF: 0.000573 AC: 24 AN: 41868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 38416

South Asian (SAS) AF: 0.00 AC: 0 AN: 82994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51448

Middle Eastern (MID) AF: 0.00164 AC: 7 AN: 4260

European-Non Finnish (NFE) AF: 0.000168 AC: 185 AN: 1102614

Other (OTH) AF: 0.000538 AC: 32 AN: 59460

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74396

African (AFR) AF: 0.0000722 AC: 3 AN: 41536

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67970

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.000280

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia 33 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.87
PhyloP100		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.028
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: rs374119905; hg19: chr16-90106923;