rs148760410

Variant names:

• chr16-90032836-G-C
• rs148760410
• NM_001481.3:c.407G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001286208.2(DRC4):​c.-115G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,613,970 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (9 hom.)
• Consequence: DRC4 NM_001286208.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.582
• Publications: 3 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]

DRC4 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 33

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00311625).
• BP6: Variant 16-90032836-G-C is Benign according to our data. Variant chr16-90032836-G-C is described in ClinVar as Benign. ClinVar VariationId is 542271.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0009 (137/152194) while in subpopulation EAS AF = 0.0189 (98/5188). AF 95% confidence interval is 0.0159. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286208.2. 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.407G>C	p.Ser136Thr	missense	Exon 4 of 11	NP_001472.1	O95995-1
	DRC4	NM_001286208.2		c.-115G>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	NP_001273137.1
	DRC4	NM_001286209.2		c.332G>C	p.Ser111Thr	missense	Exon 4 of 11	NP_001273138.1	O95995-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAS8	ENST00000268699.9	TSL:1 MANE Select	c.407G>C	p.Ser136Thr	missense	Exon 4 of 11	ENSP00000268699.4	O95995-1
	GAS8	ENST00000566266.5	TSL:1	n.*422G>C		non_coding_transcript_exon	Exon 4 of 10	ENSP00000454343.1	H3BME0
	GAS8	ENST00000566266.5	TSL:1	n.*422G>C		3_prime_UTR	Exon 4 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00176 AC: 443 AN: 251324 AF XY: 0.00163

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0199

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000754 AC: 1102 AN: 1461776 Hom.: 9 Cov.: 33 AF XY: 0.000755 AC XY: 549 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26130

East Asian (EAS) AF: 0.0150 AC: 597 AN: 39700

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86254

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53416

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

European-Non Finnish (NFE) AF: 0.000237 AC: 263 AN: 1111936

Other (OTH) AF: 0.00291 AC: 176 AN: 60390

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74404

African (AFR) AF: 0.0000241 AC: 1 AN: 41480

American (AMR) AF: 0.000850 AC: 13 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67996

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000305 Hom.: 0

Bravo AF: 0.00110

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	GAS8-related disorder (1)
-	-	1	Primary ciliary dyskinesia 33 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.8
DANN	Benign	0.51
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.58
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.022
Sift	Benign	0.60	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.30
MPC		0.017
ClinPred		0.0063	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.036
Mutation Taster		=98/2	polymorphism

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: rs148760410; hg19: chr16-90099244;