8-7055504-C-T

Position:

• chr8-7055504-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0095 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (163 hom.)
• Consequence: DEFA5 NM_021010.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.10

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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. gnomad4_exome 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 gnomad4_exome. There are 9702 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFA5	NM_021010.3	c.212G>A	p.Arg71His	missense_variant	2/2	ENST00000330590.4	NP_066290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEFA5	ENST00000330590.4	c.212G>A	p.Arg71His	missense_variant	2/2	1	NM_021010.3	ENSP00000329890.2

Frequencies

GnomAD3 genomes AF: 0.00954 AC: 1451 AN: 152092 Hom.: 9 Cov.: 32

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

GnomAD3 exomes AF: 0.00928 AC: 2320 AN: 250132 Hom.: 13 AF XY: 0.00933 AC XY: 1261 AN XY: 135210

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 SAS exome AF: 0.00279

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.: 30 AF XY: 0.0133 AC XY: 9702 AN XY: 726816

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00562

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00294

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0162

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00953 AC: 1450 AN: 152210 Hom.: 9 Cov.: 32 AF XY: 0.00958 AC XY: 713 AN XY: 74416

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0109 Hom.: 4

Bravo AF: 0.00903

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0150 AC: 129

ExAC AF: 0.00903 AC: 1097

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0120

EpiControl AF: 0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0020
DANN	Benign	0.36
DEOGEN2	Benign	0.018	T
Eigen	Benign	-2.9
Eigen_PC	Benign	-3.1
FATHMM_MKL	Benign	0.00013	N
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.049
Sift	Benign	0.54	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.070
MVP		0.15
MPC		0.00042
ClinPred		0.0049	T
GERP RS		-3.4
Varity_R		0.11
gMVP		0.14

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: rs7839771; hg19: chr8-6913026; COSMIC: COSV57962650;