8-7055504-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021010.3(DEFA5):c.212G>A(p.Arg71His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,356 control chromosomes in the GnomAD database, including 172 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0095 ( 9 hom., cov: 32)

Exomes 𝑓: 0.014 ( 163 hom. )

Consequence

DEFA5
NM_021010.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -8.10

Publications

5 publications found

Variant links:

Genes affected

DEFA5 (HGNC:2764): (defensin alpha 5) 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 of the alpha defensin genes appear to be clustered on chromosome 8. The protein encoded by this gene, defensin, alpha 5, is highly expressed in the secretory granules of Paneth cells of the ileum. [provided by RefSeq, Oct 2014]

DEFA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063924193).

BP6

Variant 8-7055504-C-T is Benign according to our data. Variant chr8-7055504-C-T is described in ClinVar as Benign. ClinVar VariationId is 780127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0137 (20027/1461146) while in subpopulation NFE AF = 0.0162 (18044/1111572). AF 95% confidence interval is 0.016. There are 163 homozygotes in GnomAdExome4. There are 9702 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021010.3. 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
	DEFA5	NM_021010.3	MANE Select	c.212G>A	p.Arg71His	missense	Exon 2 of 2	NP_066290.1	Q01523

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFA5	ENST00000330590.4	TSL:1 MANE Select	c.212G>A	p.Arg71His	missense	Exon 2 of 2	ENSP00000329890.2	Q01523

Frequencies

GnomAD3 genomes

AF:

0.00954

AC:

1451

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00928

AC:

2320

AN:

250132

AF XY:

0.00933

show subpopulations

Gnomad AFR exome

AF:

0.00236

Gnomad AMR exome

AF:

0.00574

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0147

Gnomad OTH exome

AF:

0.00953

GnomAD4 exome

AF:

0.0137

AC:

20027

AN:

1461146

Hom.:

163

Cov.:

AF XY:

0.0133

AC XY:

9702

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33478

American (AMR)

AF:

0.00562

AC:

251

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.000403

AC:

AN:

39692

South Asian (SAS)

AF:

0.00294

AC:

253

AN:

86130

European-Finnish (FIN)

AF:

0.0136

AC:

728

AN:

53348

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0162

AC:

18044

AN:

1111572

Other (OTH)

AF:

0.0111

AC:

672

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

976

1952

2929

3905

4881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

656

1312

1968

2624

3280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00953

AC:

1450

AN:

152210

Hom.:

Cov.:

AF XY:

0.00958

AC XY:

713

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00241

AC:

100

AN:

41546

American (AMR)

AF:

0.00994

AC:

152

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000582

AC:

AN:

5156

South Asian (SAS)

AF:

0.00270

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0139

AC:

147

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0149

AC:

1016

AN:

68006

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00903

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0150

AC:

129

ExAC

AF:

0.00903

AC:

1097

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0120

EpiControl

AF:

0.0142

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.0020

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.018

Eigen

Benign

-2.9

Eigen_PC

Benign

-3.1

FATHMM_MKL

Benign

0.00013

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.93

PhyloP100

-8.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.57

REVEL

Benign

0.049

Sift

Benign

0.54

Sift4G

Benign

0.54

Polyphen

0.0

Vest4

0.070

MVP

0.15

MPC

0.00042

ClinPred

0.0049

GERP RS

-3.4

Varity_R

0.11

gMVP

0.14

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over