rs779223727

Variant names:

• chr5-149027061-C-T
• rs779223727
• NM_024577.4:c.2671G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024577.4(SH3TC2):​c.2671G>A​(p.Ala891Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.00500
• Publications: 0 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), Orphanet, Ambry Genetics
• susceptibility to mononeuropathy of the median nerve, mild

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.12606594).

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.2671G>A	p.Ala891Thr	missense	Exon 11 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.2671G>A	p.Ala891Thr	missense	Exon 11 of 17	ENSP00000423660.1
	SH3TC2	ENST00000512049.5	TSL:1	c.2650G>A	p.Ala884Thr	missense	Exon 11 of 17	ENSP00000421860.1
	SH3TC2	ENST00000323829.9	TSL:1	n.*2059G>A		non_coding_transcript_exon	Exon 12 of 18	ENSP00000313025.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251052 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

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: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25 AN XY: 727220

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111998

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.8
DANN	Benign	0.75
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.0050
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.23
Sift	Benign	0.062	T
Sift4G	Benign	0.11	T
Polyphen		0.18	B
Vest4		0.065
MutPred		0.39		Gain of ubiquitination at K888 (P = 0.0817)
MVP		0.66
MPC		0.044
ClinPred		0.058	T
GERP RS		-3.9
Varity_R		0.070
gMVP		0.23
Mutation Taster		=91/9	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: rs779223727; hg19: chr5-148406624;