rs138964358

Variant names:

• chrX-1290354-G-A
• rs138964358
• NM_172245.4:c.491G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-1290354-G-A
• chrX-1290354-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001161530.2(CSF2RA):​c.491G>A​(p.Arg164Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00776 in 1,613,084 control chromosomes in the GnomAD database, including 71 homozygotes. There are 6,063 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., 365 hem., cov: 31)
  • Exomes 𝑓: 0.0080 (69 hom. 5698 hem.)
• Consequence: CSF2RA NM_001161530.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.243
• Publications: 0 publications found

Genes affected

CSF2RA (HGNC:2435): (colony stimulating factor 2 receptor subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric receptor for colony stimulating factor 2, a cytokine which controls the production, differentiation, and function of granulocytes and macrophages. The encoded protein is a member of the cytokine family of receptors. This gene is found in the pseudoautosomal region (PAR) of the X and Y chromosomes. Multiple transcript variants encoding different isoforms have been found for this gene, with some of the isoforms being membrane-bound and others being soluble. [provided by RefSeq, Jul 2008]

CSF2RA Gene-Disease associations (from GenCC):

• surfactant metabolism dysfunction, pulmonary, 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary pulmonary alveolar proteinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.014863938).
• BP6: Variant X-1290354-G-A is Benign according to our data. Variant chrX-1290354-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00532 (809/151998) while in subpopulation NFE AF = 0.00868 (590/67982). AF 95% confidence interval is 0.0081. There are 2 homozygotes in GnomAd4. There are 365 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161530.2. 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
	CSF2RA	NM_172245.4	MANE Select	c.491G>A	p.Arg164Gln	missense	Exon 7 of 13	NP_758448.1
	CSF2RA	NM_001161530.2		c.491G>A	p.Arg164Gln	missense	Exon 7 of 14	NP_001155002.1
	CSF2RA	NM_001379153.1		c.491G>A	p.Arg164Gln	missense	Exon 6 of 13	NP_001366082.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.491G>A	p.Arg164Gln	missense	Exon 7 of 13	ENSP00000370940.3
	CSF2RA	ENST00000381509.8	TSL:1	c.491G>A	p.Arg164Gln	missense	Exon 7 of 13	ENSP00000370920.3
	CSF2RA	ENST00000381524.8	TSL:1	c.491G>A	p.Arg164Gln	missense	Exon 7 of 13	ENSP00000370935.3

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 811 AN: 151886 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00190

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00868

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.00512 AC: 1285 AN: 251150 AF XY: 0.00497

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00953

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00799

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.00801 AC: 11705 AN: 1461086 Hom.: 69 Cov.: 32 AF XY: 0.00784 AC XY: 5698 AN XY: 726852

African (AFR) AF: 0.00161 AC: 54 AN: 33470

American (AMR) AF: 0.00378 AC: 169 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00877 AC: 229 AN: 26124

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.00151 AC: 130 AN: 86236

European-Finnish (FIN) AF: 0.00279 AC: 149 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.00949 AC: 10544 AN: 1111312

Other (OTH) AF: 0.00689 AC: 416 AN: 60356

GnomAD4 genome AF: 0.00532 AC: 809 AN: 151998 Hom.: 2 Cov.: 31 AF XY: 0.00491 AC XY: 365 AN XY: 74294

African (AFR) AF: 0.00178 AC: 74 AN: 41474

American (AMR) AF: 0.00341 AC: 52 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4796

European-Finnish (FIN) AF: 0.00190 AC: 20 AN: 10534

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00868 AC: 590 AN: 67982

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Bravo AF: 0.00541

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00768 AC: 66

ExAC AF: 0.00471 AC: 572

EpiCase AF: 0.00780

EpiControl AF: 0.00723

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Surfactant metabolism dysfunction, pulmonary, 4 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.19
DANN	Benign	0.88
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.00041	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	-0.28	N
PhyloP100		-0.24
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.13
Sift	Benign	0.14	T
Sift4G	Uncertain	0.042	D
Polyphen		0.93	P
Vest4		0.12
MVP		0.49
MPC		0.14
ClinPred		0.012	T
GERP RS		-0.36
Varity_R		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138964358; hg19: chrX-1409247;