20-31377280-C-G

Variant names:

• chr20-31377280-C-G
• NM_153289.4:c.221G>C

Variant summary

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

The NM_153289.4(DEFB119):​c.221G>C​(p.Trp74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/19 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)
• Consequence: DEFB119 NM_153289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.864
• Publications: 0 publications found

Genes affected

DEFB119 (HGNC:18099): (defensin beta 119) This gene encodes a member of the beta subfamily of defensins. Beta-defensins are antimicrobial peptides that protect tissues and organs from infection by a variety of microorganisms. This gene is found in a cluster with other beta-defensin genes on the long arm of chromosome 20. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2014]

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB119	NM_153289.4	c.221G>C	p.Trp74Ser	missense_variant	Exon 2 of 2	ENST00000376321.4	NP_695021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFB119	ENST00000376321.4	c.221G>C	p.Trp74Ser	missense_variant	Exon 2 of 2	1	NM_153289.4	ENSP00000365499.3
DEFB119	ENST00000339144.3	c.*129G>C		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000345768.3
DEFB119	ENST00000492344.1	n.384G>C		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.221G>C (p.W74S) alteration is located in exon 2 (coding exon 2) of the DEFB119 gene. This alteration results from a G to C substitution at nucleotide position 221, causing the tryptophan (W) at amino acid position 74 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T
Eigen	Benign	0.058
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.58	T
PhyloP100		0.86
PROVEAN	Pathogenic	-14	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.46		Gain of disorder (P = 0.0017);
MVP		0.24
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.23
Mutation Taster		=92/8	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

hg19: chr20-29965083;