rs374027741

Variant names:

• chr8-11984519-C-A
• rs374027741
• NM_001033017.3:c.163C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-11984519-C-A
• chr8-11984519-C-G
• chr8-11984519-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001033017.3(DEFB135):​c.163C>A​(p.Arg55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DEFB135 NM_001033017.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.516
• Publications: 0 publications found

Genes affected

DEFB135 (HGNC:32400): (defensin beta 135) Defensins are cysteine-rich cationic polypeptides that are important in the immunologic response to invading microorganisms. The antimicrobial protein encoded by this gene is secreted and is a member of the beta defensin protein family. Beta defensin genes are found in several clusters throughout the genome, with this gene mapping to a cluster at 8p23. [provided by RefSeq, Nov 2014]

ENSG00000290829 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07623646).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033017.3. 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
	DEFB135	NM_001033017.3	MANE Select	c.163C>A	p.Arg55Ser	missense	Exon 2 of 2	NP_001028189.2	Q30KP9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFB135	ENST00000382208.3	TSL:1 MANE Select	c.163C>A	p.Arg55Ser	missense	Exon 2 of 2	ENSP00000371643.2	Q30KP9
	ENSG00000290829	ENST00000715788.1		n.297+30312G>T		intron	N/A
	ENSG00000290829	ENST00000715789.1		n.333+30312G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434116 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709656

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32972

American (AMR) AF: 0.00 AC: 0 AN: 44048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38970

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090888

Other (OTH) AF: 0.00 AC: 0 AN: 59048

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.038	N
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.52
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.067
Sift	Benign	0.12	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.32
MutPred		0.46		Gain of ubiquitination at K50 (P = 0.0758)
MVP		0.040
MPC		0.0072
ClinPred		0.57	D
GERP RS		3.3
Varity_R		0.15
gMVP		0.27
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: rs374027741; hg19: chr8-11842028;