4-8212818-G-A

Variant names:

• chr4-8212818-G-A
• rs200305611
• NM_018986.5:c.365G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018986.5(SH3TC1):​c.365G>A​(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,583,890 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: SH3TC1 NM_018986.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.275
• Publications: 5 publications found

Genes affected

SH3TC1 (HGNC:26009): (SH3 domain and tetratricopeptide repeats 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.011543393).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018986.5. 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
	SH3TC1	NM_018986.5	MANE Select	c.365G>A	p.Arg122His	missense	Exon 4 of 18	NP_061859.4
	SH3TC1	NM_001410712.1		c.365G>A	p.Arg122His	missense	Exon 4 of 18	NP_001397641.1	A0A804HI81
	SH3TC1	NM_001318480.2		c.137G>A	p.Arg46His	missense	Exon 4 of 18	NP_001305409.2	H0YA34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC1	ENST00000245105.8	TSL:2 MANE Select	c.365G>A	p.Arg122His	missense	Exon 4 of 18	ENSP00000245105.3	Q8TE82
	SH3TC1	ENST00000502669.5	TSL:1	n.290G>A		non_coding_transcript_exon	Exon 3 of 15	ENSP00000425970.1	D6RI07
	SH3TC1	ENST00000457650.7	TSL:5	c.365G>A	p.Arg122His	missense	Exon 5 of 19	ENSP00000390311.3	Q8TE82

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152214 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000514 AC: 101 AN: 196640 AF XY: 0.000546

Gnomad AFR exome AF: 0.000257

Gnomad AMR exome AF: 0.000172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.00104 AC: 1486 AN: 1431558 Hom.: 4 Cov.: 32 AF XY: 0.00103 AC XY: 731 AN XY: 709432

African (AFR) AF: 0.000212 AC: 7 AN: 33042

American (AMR) AF: 0.000296 AC: 12 AN: 40522

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25232

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38524

South Asian (SAS) AF: 0.000146 AC: 12 AN: 82008

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50866

Middle Eastern (MID) AF: 0.000195 AC: 1 AN: 5130

European-Non Finnish (NFE) AF: 0.00128 AC: 1402 AN: 1097142

Other (OTH) AF: 0.000778 AC: 46 AN: 59092

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152332 Hom.: 0 Cov.: 34 AF XY: 0.000618 AC XY: 46 AN XY: 74492

African (AFR) AF: 0.000168 AC: 7 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15308

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

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000882 Hom.: 0

Bravo AF: 0.000688

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000817 AC: 7

ExAC AF: 0.000416 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.28
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.072
Sift	Benign	0.25	T
Sift4G	Benign	0.26	T
Polyphen		0.052	B
Vest4		0.21
MVP		0.47
MPC		0.032
ClinPred		0.0060	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.18
Mutation Taster		=100/0	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: rs200305611; hg19: chr4-8214545; COSMIC: COSV55288627; COSMIC: COSV55288627;