rs147633804

Variant names:

• chr5-149042706-G-T
• rs147633804
• NM_024577.4:c.517C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_024577.4(SH3TC2):​c.517C>A​(p.Leu173Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 1.95
• Publications: 3 publications found

Genes affected

SH3TC2 (HGNC:29427): (SH3 domain and tetratricopeptide repeats 2) This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. [provided by RefSeq, Jul 2008]

SH3TC2 Gene-Disease associations (from GenCC):

• autosomal recessive hereditary demyelinating motor and sensory neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• susceptibility to mononeuropathy of the median nerve, mild

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024577.4. 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
	SH3TC2	NM_024577.4	MANE Select	c.517C>A	p.Leu173Met	missense	Exon 5 of 17	NP_078853.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.517C>A	p.Leu173Met	missense	Exon 5 of 17	ENSP00000423660.1	Q8TF17-1
	SH3TC2	ENST00000512049.5	TSL:1	c.496C>A	p.Leu166Met	missense	Exon 5 of 17	ENSP00000421860.1	Q8TF17-5
	SH3TC2	ENST00000323829.9	TSL:1	n.517C>A		non_coding_transcript_exon	Exon 5 of 18	ENSP00000313025.5	D6RA65

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251424 AF XY: 0.0000957

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000648 AC: 72 AN: 1111964

Other (OTH) AF: 0.0000828 AC: 5 AN: 60388

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74346

African (AFR) AF: 0.0000483 AC: 2 AN: 41434

American (AMR) AF: 0.000196 AC: 3 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	1	-	Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.79
MPC		0.28
ClinPred		0.45	T
GERP RS		3.4
Varity_R		0.27
gMVP		0.54
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147633804; hg19: chr5-148422269;