chr16-89949614-C-T

Variant names:

• chr16-89949614-C-T
• rs2031584868
• NM_001242818.2:c.-11+101C>T

Variant summary

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

The NM_207514.3(DEF8):​c.149C>T​(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DEF8 NM_207514.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.104
• Publications: 0 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: 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 (MetaRNN=0.058641076).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207514.3. 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
	DEF8	NM_001242818.2	MANE Select	c.-11+101C>T		intron	N/A	NP_001229747.1	Q6ZN54-5
	DEF8	NM_001438955.1		c.149C>T	p.Ala50Val	missense	Exon 2 of 13	NP_001425884.1
	DEF8	NM_207514.3		c.149C>T	p.Ala50Val	missense	Exon 2 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.-11+101C>T		intron	N/A	ENSP00000458019.1	Q6ZN54-5
	DEF8	ENST00000610455.4	TSL:1	c.-11+800C>T		intron	N/A	ENSP00000480073.1	Q6ZN54-2
	DEF8	ENST00000567999.5	TSL:1	c.-11+800C>T		intron	N/A	ENSP00000457072.1	H3BT87

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248682 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460334 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726452

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111590

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.092
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.10
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.057
Sift	Benign	0.11	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.18		Gain of stability (P = 0.0265)
MVP		0.030
MPC		0.050
ClinPred		0.11	T
GERP RS		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.050
gMVP		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2031584868; hg19: chr16-90016022;