NM_014332.3:c.132G>A

Variant names:

• chrX-21743750-C-T
• rs199907508
• NM_014332.3:c.132G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_014332.3(SMPX):​c.132G>A​(p.Glu44Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000631 in 1,198,986 control chromosomes in the GnomAD database, including 1 homozygotes. There are 235 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.00064 (1 hom. 217 hem.)
• Consequence: SMPX NM_014332.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.87
• Publications: 2 publications found

Genes affected

SMPX (HGNC:11122): (small muscle protein X-linked) This gene encodes a small protein that has no known functional domains. Mutations in this gene are a cause of X-linked deafness-4, and the encoded protein may play a role in the maintenance of inner ear cells subjected to mechanical stress. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2011]

SMPX Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, X-linked 4

  Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• myopathy, distal, 7, adult-onset, X-linked

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• X-linked nonsyndromic hearing loss

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-21743750-C-T is Benign according to our data. Variant chrX-21743750-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368152.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00052 (58/111466) while in subpopulation NFE AF = 0.000924 (49/53055). AF 95% confidence interval is 0.000717. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014332.3. 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
	SMPX	NM_014332.3	MANE Select	c.132G>A	p.Glu44Glu	splice_region synonymous	Exon 3 of 5	NP_055147.1	Q9UHP9
	SMPX	NR_045617.2		n.319G>A		splice_region non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPX	ENST00000379494.4	TSL:1 MANE Select	c.132G>A	p.Glu44Glu	splice_region synonymous	Exon 3 of 5	ENSP00000368808.3	Q9UHP9
	SMPX	ENST00000646008.1		c.132G>A	p.Glu44Glu	splice_region synonymous	Exon 3 of 5	ENSP00000493671.1	Q9UHP9
	SMPX	ENST00000867835.1		c.132G>A	p.Glu44Glu	splice_region synonymous	Exon 4 of 6	ENSP00000537894.1

Frequencies

GnomAD3 genomes AF: 0.000521 AC: 58 AN: 111412 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000386

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000923

Gnomad OTH AF: 0.000671

GnomAD2 exomes AF: 0.000399 AC: 73 AN: 183007 AF XY: 0.000340

Gnomad AFR exome AF: 0.000152

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: 0.000846

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000642 AC: 698 AN: 1087520 Hom.: 1 Cov.: 28 AF XY: 0.000613 AC XY: 217 AN XY: 353784

African (AFR) AF: 0.000153 AC: 4 AN: 26210

American (AMR) AF: 0.00 AC: 0 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19323

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.00 AC: 0 AN: 53915

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40503

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 0.000808 AC: 673 AN: 832409

Other (OTH) AF: 0.000437 AC: 20 AN: 45729

GnomAD4 genome AF: 0.000520 AC: 58 AN: 111466 Hom.: 0 Cov.: 23 AF XY: 0.000535 AC XY: 18 AN XY: 33662

African (AFR) AF: 0.000195 AC: 6 AN: 30720

American (AMR) AF: 0.00 AC: 0 AN: 10489

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.000387 AC: 1 AN: 2586

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000924 AC: 49 AN: 53055

Other (OTH) AF: 0.000662 AC: 1 AN: 1510

Alfa AF: 0.000746 Hom.: 30

Bravo AF: 0.000480

EpiCase AF: 0.000437

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Hearing loss, X-linked 4 (1)
-	-	1	SMPX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.91
PhyloP100		5.9
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199907508; hg19: chrX-21761868;