chr16-89954283-C-T

Variant names:

• chr16-89954283-C-T
• rs776085470
• NM_001242818.2:c.31C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001242818.2(DEF8):​c.31C>T​(p.Arg11Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,461,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DEF8 NM_001242818.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90
• Publications: 4 publications found

Genes affected

DEF8 (HGNC:25969): (differentially expressed in FDCP 8 homolog) Predicted to enable metal ion binding activity. Predicted to be involved in lysosome localization; positive regulation of bone resorption; and positive regulation of ruffle assembly. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242818.2. 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
	DEF8	NM_001242818.2	MANE Select	c.31C>T	p.Arg11Trp	missense	Exon 3 of 13	NP_001229747.1	Q6ZN54-5
	DEF8	NM_001438955.1		c.214C>T	p.Arg72Trp	missense	Exon 3 of 13	NP_001425884.1
	DEF8	NM_207514.3		c.214C>T	p.Arg72Trp	missense	Exon 3 of 13	NP_997397.1	Q6ZN54-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEF8	ENST00000563594.6	TSL:1 MANE Select	c.31C>T	p.Arg11Trp	missense	Exon 3 of 13	ENSP00000458019.1	Q6ZN54-5
	DEF8	ENST00000610455.4	TSL:1	c.31C>T	p.Arg11Trp	missense	Exon 2 of 5	ENSP00000480073.1	Q6ZN54-2
	DEF8	ENST00000567999.5	TSL:1	c.31C>T	p.Arg11Trp	missense	Exon 2 of 5	ENSP00000457072.1	H3BT87

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250704 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461190 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726868

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5434

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111970

Other (OTH) AF: 0.0000166 AC: 1 AN: 60332

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.096	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.51		Loss of disorder (P = 0.0034)
MVP		0.75
MPC		0.34
ClinPred		0.88	D
GERP RS		5.1
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.61
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776085470; hg19: chr16-90020691; COSMIC: COSV51919754; COSMIC: COSV51919754;