chr4-9444586-C-T

Variant names:

• chr4-9444586-C-T
• rs777237570
• NM_001040448.3:c.53C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001040448.3(DEFB131A):​c.53C>T​(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,577,836 control chromosomes in the GnomAD database, including 1 homozygotes. 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. P18S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000067 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DEFB131A NM_001040448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0170
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07892606).

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.53C>T	p.Pro18Leu	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.53C>T	p.Pro18Leu	missense	Exon 1 of 2	ENSP00000335538.1	P59861

Frequencies

GnomAD3 genomes AF: 0.0000673 AC: 8 AN: 118910 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000101

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: 0.0000972

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000591 AC: 14 AN: 236908 AF XY: 0.0000854

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: 0.000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1458926 Hom.: 0 Cov.: 29 AF XY: 0.0000937 AC XY: 68 AN XY: 725780

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

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

European-Non Finnish (NFE) AF: 0.000140 AC: 156 AN: 1111534

Other (OTH) AF: 0.000150 AC: 9 AN: 60170

GnomAD4 genome AF: 0.0000673 AC: 8 AN: 118910 Hom.: 1 Cov.: 33 AF XY: 0.0000348 AC XY: 2 AN XY: 57528

African (AFR) AF: 0.0000539 AC: 2 AN: 37080

American (AMR) AF: 0.000101 AC: 1 AN: 9924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2458

East Asian (EAS) AF: 0.00 AC: 0 AN: 4292

South Asian (SAS) AF: 0.00 AC: 0 AN: 3504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000972 AC: 5 AN: 51438

Other (OTH) AF: 0.00 AC: 0 AN: 1488

Alfa AF: 0.0000988 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000414 AC: 5

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	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.00062	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.017
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.053
Sift	Benign	0.31	T
Sift4G	Benign	0.34	T
Polyphen		0.0080	B
Vest4		0.29
MVP		0.014
MPC		0.00037
ClinPred		0.054	T
GERP RS		-0.74
PromoterAI		-0.0060	Neutral
Varity_R		0.068
gMVP		0.071
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: rs777237570; hg19: chr4-9446312;