chr8-6936739-A-G

Variant names:

• chr8-6936739-A-G
• rs753521273
• NM_001925.3:c.161T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001925.3(DEFA4):​c.161T>C​(p.Leu54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,599,862 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: DEFA4 NM_001925.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.948

Genes affected

DEFA4 (HGNC:2763): (defensin alpha 4) Defensins are a family of antimicrobial and cytotoxic peptides thought to be involved in host defense. They are abundant in the granules of neutrophils and also found in the epithelia of mucosal surfaces such as those of the intestine, respiratory tract, urinary tract, and vagina. Members of the defensin family are highly similar in protein sequence and distinguished by a conserved cysteine motif. Several alpha defensin genes are clustered on chromosome 8. This gene differs from other genes of this family by an extra 83-base segment that is apparently the result of a recent duplication within the coding region. The protein encoded by this gene, defensin, alpha 4, is found in the neutrophils; it exhibits corticostatic activity and inhibits corticotropin stimulated corticosterone production. [provided by RefSeq, Oct 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37544036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFA4	NM_001925.3	c.161T>C	p.Leu54Pro	missense_variant	Exon 2 of 3	ENST00000297435.3	NP_001916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFA4	ENST00000297435.3	c.161T>C	p.Leu54Pro	missense_variant	Exon 2 of 3	1	NM_001925.3	ENSP00000297435.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000205 AC: 5 AN: 244074 AF XY: 0.00000758

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: 0.0000465

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 21 AN: 1447684 Hom.: 0 Cov.: 31 AF XY: 0.0000167 AC XY: 12 AN XY: 718550

African (AFR) AF: 0.00 AC: 0 AN: 32974

American (AMR) AF: 0.00 AC: 0 AN: 43622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39208

South Asian (SAS) AF: 0.00 AC: 0 AN: 84074

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1103480

Other (OTH) AF: 0.0000168 AC: 1 AN: 59644

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161T>C (p.L54P) alteration is located in exon 2 (coding exon 1) of the DEFA4 gene. This alteration results from a T to C substitution at nucleotide position 161, causing the leucine (L) at amino acid position 54 to be replaced by a proline (P). 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	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.7
DANN	Benign	0.58
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0013	N
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.16
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.35	B
Vest4		0.54
MutPred		0.66		Loss of stability (P = 0.0037);
MVP		0.13
MPC		0.0011
ClinPred		0.10	T
GERP RS		-3.0
Varity_R		0.68
gMVP		0.17
Mutation Taster		=90/10	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

Publications

LitVar

Other links and lift over

dbSNP: rs753521273; hg19: chr8-6794261; COSMIC: COSV52404706;