X-65716877-C-A

Variant names:

• chrX-65716877-C-A
• rs772035472
• NM_002444.3:c.72C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_002444.3(MSN):​c.72C>A​(p.Thr24Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,207,785 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MSN NM_002444.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.176
• Publications: 0 publications found

Genes affected

MSN (HGNC:7373): (moesin) Moesin (for membrane-organizing extension spike protein) is a member of the ERM family which includes ezrin and radixin. ERM proteins appear to function as cross-linkers between plasma membranes and actin-based cytoskeletons. Moesin is localized to filopodia and other membranous protrusions that are important for cell-cell recognition and signaling and for cell movement. [provided by RefSeq, Jul 2008]

MSN Gene-Disease associations (from GenCC):

• combined immunodeficiency due to moesin deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-65716877-C-A is Benign according to our data. Variant chrX-65716877-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3616888.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.176 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002444.3. 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
	MSN	NM_002444.3	MANE Select	c.72C>A	p.Thr24Thr	synonymous	Exon 2 of 13	NP_002435.1	P26038
	MSN	NM_001440778.1		c.75C>A	p.Thr25Thr	synonymous	Exon 2 of 13	NP_001427707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSN	ENST00000360270.7	TSL:1 MANE Select	c.72C>A	p.Thr24Thr	synonymous	Exon 2 of 13	ENSP00000353408.5	P26038
	MSN	ENST00000943362.1		c.72C>A	p.Thr24Thr	synonymous	Exon 3 of 14	ENSP00000613421.1
	MSN	ENST00000915048.1		c.72C>A	p.Thr24Thr	synonymous	Exon 2 of 13	ENSP00000585107.1

Frequencies

GnomAD3 genomes AF: 0.00000910 AC: 1 AN: 109889 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000332

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

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183089 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097896 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 363286

African (AFR) AF: 0.0000379 AC: 1 AN: 26390

American (AMR) AF: 0.00 AC: 0 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841851

Other (OTH) AF: 0.00 AC: 0 AN: 46090

GnomAD4 genome AF: 0.00000910 AC: 1 AN: 109889 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32109

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

African (AFR) AF: 0.0000332 AC: 1 AN: 30133

American (AMR) AF: 0.00 AC: 0 AN: 10244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00 AC: 0 AN: 2468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5847

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52659

Other (OTH) AF: 0.00 AC: 0 AN: 1477

⚠️ 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.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.7
DANN	Benign	0.61
PhyloP100		0.18

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: rs772035472; hg19: chrX-64936739;