4-9444585-C-T

Variant names:

• chr4-9444585-C-T
• rs758097415
• NM_001040448.3:c.52C>T

Variant summary

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

The NM_001040448.3(DEFB131A):​c.52C>T​(p.Pro18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000633 in 1,580,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P18L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000083 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DEFB131A NM_001040448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0260
• Publications: 1 publications found

Genes affected

DEFB131A (HGNC:18108): (defensin beta 131A) 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 4p16. [provided by RefSeq, Nov 2014]

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=0.140457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040448.3. 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
	DEFB131A	NM_001040448.3	MANE Select	c.52C>T	p.Pro18Ser	missense	Exon 1 of 2	NP_001035538.2	P59861

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFB131A	ENST00000334879.2	TSL:1 MANE Select	c.52C>T	p.Pro18Ser	missense	Exon 1 of 2	ENSP00000335538.1	P59861

Frequencies

GnomAD3 genomes AF: 0.00000825 AC: 1 AN: 121164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 237878 AF XY: 0.00000774

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: 0.00000921

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458924 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 725786

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111522

Other (OTH) AF: 0.0000166 AC: 1 AN: 60170

GnomAD4 genome AF: 0.00000825 AC: 1 AN: 121164 Hom.: 0 Cov.: 33 AF XY: 0.0000171 AC XY: 1 AN XY: 58622

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

African (AFR) AF: 0.0000268 AC: 1 AN: 37318

American (AMR) AF: 0.00 AC: 0 AN: 10198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2524

East Asian (EAS) AF: 0.00 AC: 0 AN: 4344

South Asian (SAS) AF: 0.00 AC: 0 AN: 3570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52816

Other (OTH) AF: 0.00 AC: 0 AN: 1510

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

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	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.7
DANN	Benign	0.96
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.00061	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.026
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.034
Sift	Benign	0.33	T
Sift4G	Benign	0.85	T
Polyphen		0.90	P
Vest4		0.38
MutPred		0.43		Loss of loop (P = 0.0203)
MVP		0.014
MPC		0.00037
ClinPred		0.18	T
GERP RS		0.31
PromoterAI		-0.027	Neutral
Varity_R		0.052
gMVP		0.085
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: rs758097415; hg19: chr4-9446311; COSMIC: COSV58416781;