4-173391288-C-T

Variant names:

• chr4-173391288-C-T
• rs761778143
• NM_007281.4:c.127G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007281.4(SCRG1):​c.127G>A​(p.Glu43Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E43Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCRG1 NM_007281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.29
• Publications: 0 publications found

Genes affected

SCRG1 (HGNC:17036): (stimulator of chondrogenesis 1) Scrapie-responsive gene 1 is associated with neurodegenerative changes observed in transmissible spongiform encephalopathies. It may play a role in host response to prion-associated infections. The scrapie responsive protein 1 may be partly included in the membrane or secreted by the cells due to its hydrophobic N-terminus. In addition, the encoded protein can interact with bone marrow stromal cell antigen 1 (BST1) to enhance the differentiation potentials of human mesenchymal stem cells during tissue and bone regeneration. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28459668).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007281.4. 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
	SCRG1	NM_007281.4	MANE Select	c.127G>A	p.Glu43Lys	missense	Exon 2 of 3	NP_009212.1	Q6FGG5
	SCRG1	NM_001329597.2		c.127G>A	p.Glu43Lys	missense	Exon 3 of 4	NP_001316526.1	O75711

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCRG1	ENST00000296506.8	TSL:1 MANE Select	c.127G>A	p.Glu43Lys	missense	Exon 2 of 3	ENSP00000296506.2	O75711
	SCRG1	ENST00000883955.1		c.127G>A	p.Glu43Lys	missense	Exon 2 of 3	ENSP00000554014.1
	SCRG1	ENST00000512188.1	TSL:2	n.127G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000425404.1	D6RD99

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.68	T
PhyloP100		3.3
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.12
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.039	D
Polyphen		0.79	P
Vest4		0.44
MutPred		0.25		Gain of ubiquitination at E43 (P = 0.0276)
MVP		0.50
MPC		0.45
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.37
gMVP		0.64
Mutation Taster		=85/15	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: rs761778143; hg19: chr4-174312439;