1-36319268-G-C

Position:

• chr1-36319268-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001162530.2(SH3D21):​c.872G>C​(p.Arg291Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,399,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: SH3D21 NM_001162530.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.155

Genes affected

SH3D21 (HGNC:26236): (SH3 domain containing 21) Located in nucleoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049587637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3D21	NM_001162530.2	c.872G>C	p.Arg291Pro	missense_variant	12/16	ENST00000453908.8	NP_001156002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3D21	ENST00000453908.8	c.872G>C	p.Arg291Pro	missense_variant	12/16	5	NM_001162530.2	ENSP00000403476	P1
SH3D21	ENST00000505871.7	c.539G>C	p.Arg180Pro	missense_variant	9/13	2		ENSP00000421294
SH3D21	ENST00000508854.2	n.42G>C		non_coding_transcript_exon_variant	2/3	5
SH3D21	ENST00000480549.6	c.383+104G>C		intron_variant, NMD_transcript_variant		2		ENSP00000425484

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1399404 Hom.: 0 Cov.: 32 AF XY: 0.00000580 AC XY: 4 AN XY: 690210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000834

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.872G>C (p.R291P) alteration is located in exon 12 (coding exon 12) of the SH3D21 gene. This alteration results from a G to C substitution at nucleotide position 872, causing the arginine (R) at amino acid position 291 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.1
DANN	Benign	0.96
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.026
Sift	Benign	0.27	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.98	.;D
Vest4		0.077
MVP		0.072
MPC		0.33
ClinPred		0.25	T
GERP RS		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs141873075; hg19: chr1-36784869;