4-169116383-C-A

Position:

• chr4-169116383-C-A

Variant summary

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

The NM_020870.4(SH3RF1):​c.2025G>T​(p.Glu675Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3RF1 NM_020870.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.119

Genes affected

SH3RF1 (HGNC:17650): (SH3 domain containing ring finger 1) This gene encodes a protein containing an N-terminus RING-finger, four SH3 domains, and a region implicated in binding of the Rho GTPase Rac. Via the RING-finger, the encoded protein has been shown to function as an ubiquitin-protein ligase involved in protein sorting at the trans-Golgi network. The encoded protein may also act as a scaffold for the c-Jun N-terminal kinase signaling pathway, facilitating the formation of a functional signaling module. [provided by RefSeq, Jul 2008]

SH3RF1 (HGNC:):

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=0.048470765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3RF1	NM_020870.4	c.2025G>T	p.Glu675Asp	missense_variant	10/12	ENST00000284637.14	NP_065921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3RF1	ENST00000284637.14	c.2025G>T	p.Glu675Asp	missense_variant	10/12	1	NM_020870.4	ENSP00000284637.9
SH3RF1	ENST00000508685.1	n.1906G>T		non_coding_transcript_exon_variant	9/9	1
SH3RF1	ENST00000511421.5	n.*632G>T		non_coding_transcript_exon_variant	8/8	1		ENSP00000426418.1
SH3RF1	ENST00000511421.5	n.*632G>T		3_prime_UTR_variant	8/8	1		ENSP00000426418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 26, 2024

The c.2025G>T (p.E675D) alteration is located in exon 10 (coding exon 9) of the SH3RF1 gene. This alteration results from a G to T substitution at nucleotide position 2025, causing the glutamic acid (E) at amino acid position 675 to be replaced by an aspartic acid (D). 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
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.3
DANN	Benign	0.69
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.10
Sift	Benign	0.72	T
Sift4G	Benign	0.37	T
Polyphen		0.022	B
Vest4		0.050
MutPred		0.13		Loss of solvent accessibility (P = 0.1813);
MVP		0.28
MPC		0.31
ClinPred		0.20	T
GERP RS		3.8
Varity_R		0.077
gMVP		0.063

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-170037534;