rs537950944

Variant names:

• chr14-69209669-A-G
• rs537950944
• NM_001193360.2:c.199A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001193360.2(EXD2):​c.199A>G​(p.Arg67Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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)
• Consequence: EXD2 NM_001193360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17
• Publications: 1 publications found

Genes affected

EXD2 (HGNC:20217): (exonuclease 3'-5' domain containing 2) Enables 3'-5' exonuclease activity; metal ion binding activity; and protein homodimerization activity. Involved in nucleic acid metabolic process. Located in intermediate filament cytoskeleton; mitochondrial outer membrane; and site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

GALNT16-AS1 (HGNC:55435): (GALNT16 and EXD2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0535672).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193360.2. 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
	EXD2	NM_001193360.2	MANE Select	c.199A>G	p.Arg67Gly	missense	Exon 3 of 10	NP_001180289.1	Q9NVH0-1
	EXD2	NM_001193361.2		c.199A>G	p.Arg67Gly	missense	Exon 2 of 9	NP_001180290.1	Q9NVH0-1
	EXD2	NM_001193362.2		c.199A>G	p.Arg67Gly	missense	Exon 3 of 10	NP_001180291.1	Q9NVH0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXD2	ENST00000685843.1	MANE Select	c.199A>G	p.Arg67Gly	missense	Exon 3 of 10	ENSP00000510642.1	Q9NVH0-1
	EXD2	ENST00000409018.7	TSL:1	c.199A>G	p.Arg67Gly	missense	Exon 2 of 9	ENSP00000387331.3	Q9NVH0-1
	EXD2	ENST00000413191.1	TSL:1	c.-267A>G		5_prime_UTR	Exon 3 of 6	ENSP00000409089.1	C9JLF4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74458

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.066
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.47
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.11
Sift	Benign	0.081	T
Sift4G	Benign	0.29	T
Vest4		0.086
MutPred		0.39		Loss of solvent accessibility (P = 0.0329)
MVP		0.38
MPC		0.19
ClinPred		0.041	T
GERP RS		1.6
Varity_R		0.043
gMVP		0.36
Mutation Taster		=94/6	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: rs537950944; hg19: chr14-69676386;