8-6870790-T-C

Position:

• chr8-6870790-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005218.4(DEFB1):​c.98A>G​(p.Asp33Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DEFB1 NM_005218.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

DEFB1 (HGNC:2766): (defensin beta 1) Defensins form a family of microbicidal and cytotoxic peptides made by neutrophils. Members of the defensin family are highly similar in protein sequence. This gene encodes defensin, beta 1, an antimicrobial peptide implicated in the resistance of epithelial surfaces to microbial colonization. This gene maps in close proximity to defensin family member, defensin, alpha 1 and has been implicated in the pathogenesis of cystic fibrosis. [provided by RefSeq, Jul 2008]

GS1-24F4.2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFB1	NM_005218.4	c.98A>G	p.Asp33Gly	missense_variant	2/2	ENST00000297439.4	NP_005209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEFB1	ENST00000297439.4	c.98A>G	p.Asp33Gly	missense_variant	2/2	1	NM_005218.4	ENSP00000297439.3
GS1-24F4.2	ENST00000531701.1	n.226-14332T>C		intron_variant		3
GS1-24F4.2	ENST00000655804.1	n.323-2391T>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2024

The c.98A>G (p.D33G) alteration is located in exon 2 (coding exon 2) of the DEFB1 gene. This alteration results from a A to G substitution at nucleotide position 98, causing the aspartic acid (D) at amino acid position 33 to be replaced by a glycine (G). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.028	N
M_CAP	Benign	0.0081	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.77		Loss of stability (P = 0.0447);
MVP		0.17
MPC		0.00027
ClinPred		0.94	D
GERP RS		3.0
Varity_R		0.93
gMVP		0.34

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-6728312;