21-17565577-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001338.5(CXADR):c.983G>A(p.Arg328His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,452 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CXADR NM_001338.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

CXADR (HGNC:2559): (CXADR Ig-like cell adhesion molecule) The protein encoded by this gene is a type I membrane receptor for group B coxsackieviruses and subgroup C adenoviruses. Several transcript variants encoding different isoforms have been found for this gene. Pseudogenes of this gene are found on chromosomes 15, 18, and 21. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007686883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CXADR	NM_001338.5	c.983G>A	p.Arg328His	missense_variant	7/7	ENST00000284878.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CXADR	ENST00000284878.12	c.983G>A	p.Arg328His	missense_variant	7/7	1	NM_001338.5	P2
CXADR	ENST00000400166.5	c.721G>A	p.Ala241Thr	missense_variant	5/5	1
CXADR	ENST00000400165.5	c.565G>A	p.Ala189Thr	missense_variant	4/4	1
CXADR	ENST00000400169.1	c.983G>A	p.Arg328His	missense_variant	7/8	5		A1

Frequencies

GnomAD3 genomes AF: 0.000803 AC: 122 AN: 151976 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.000968 AC: 243 AN: 251134 Hom.: 1 AF XY: 0.00111 AC XY: 151 AN XY: 135718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00132 AC: 1934 AN: 1461358 Hom.: 2 Cov.: 33 AF XY: 0.00139 AC XY: 1012 AN XY: 727004

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.000802 AC: 122 AN: 152094 Hom.: 0 Cov.: 31 AF XY: 0.000928 AC XY: 69 AN XY: 74364

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.000876

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00101 AC: 123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.983G>A (p.R328H) alteration is located in exon 7 (coding exon 7) of the CXADR gene. This alteration results from a G to A substitution at nucleotide position 983, causing the arginine (R) at amino acid position 328 to be replaced by a histidine (H). 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	0.084
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Benign	0.97
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.98	D;D;D;N;N
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.18
Sift	Benign	0.040	D;D
Polyphen		0.0080	B;B
Vest4		0.13
MVP		0.92
ClinPred		0.012	T
GERP RS		0.80

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: rs143764073; hg19: chr21-18937895; COSMIC: COSV99514937; COSMIC: COSV99514937;