rs137852860

Variant names:

• chr7-40459197-C-T
• rs137852860
• NM_001193313.2:c.985C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-40459197-C-T
• chr7-40459197-C-A
• chr7-40459197-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PS3 BP4_Strong BS2

The NM_001193313.2(SUGCT):​c.985C>T​(p.Arg329Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,578,104 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV003928585: The variant prevents the synthesis of soluble C7orf10 protein (Marlaire_2014)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R329Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (28 hom.)
• Consequence: SUGCT NM_001193313.2 missense, splice_region
• Scores: Splicing: ADA: 0.0003452
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 B:1 O:1
• Conservation: PhyloP100: 0.756
• Publications: 19 publications found

Genes affected

SUGCT (HGNC:16001): (succinyl-CoA:glutarate-CoA transferase) This gene encodes a protein that is similar to members of the CaiB/baiF CoA-transferase protein family. Mutations in this gene are associated with glutaric aciduria type III. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

SUGCT Gene-Disease associations (from GenCC):

• glutaric acidemia type 3

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003928585: The variant prevents the synthesis of soluble C7orf10 protein (Marlaire_2014).; SCV004117197: An in vitro study suggested that the p.Arg336Trp substitution impairs protein folding (Marlaire et al. 2014. PubMed ID: 23893049).
• BP4: Computational evidence support a benign effect (MetaRNN=0.057564437).
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193313.2. 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
	SUGCT	NM_001193313.2	MANE Select	c.985C>T	p.Arg329Trp	missense splice_region	Exon 11 of 14	NP_001180242.2	Q9HAC7-1
	SUGCT	NM_001193311.2		c.985C>T	p.Arg329Trp	missense splice_region	Exon 11 of 15	NP_001180240.2	Q9HAC7-3
	SUGCT	NM_024728.3		c.874C>T	p.Arg292Trp	missense splice_region	Exon 11 of 15	NP_079004.2	Q9HAC7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUGCT	ENST00000335693.9	TSL:1 MANE Select	c.985C>T	p.Arg329Trp	missense splice_region	Exon 11 of 14	ENSP00000338475.5	Q9HAC7-1
	SUGCT	ENST00000628514.3	TSL:1	c.985C>T	p.Arg329Trp	missense splice_region	Exon 11 of 15	ENSP00000486291.2	Q9HAC7-3
	SUGCT	ENST00000416370.2	TSL:1	c.985C>T	p.Arg329Trp	missense splice_region	Exon 11 of 13	ENSP00000393032.2	H0Y4N1

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152036 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00605

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00463 AC: 1135 AN: 245402 AF XY: 0.00452

Gnomad AFR exome AF: 0.000913

Gnomad AMR exome AF: 0.000383

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.00632

Gnomad NFE exome AF: 0.00828

Gnomad OTH exome AF: 0.00403

GnomAD4 exome AF: 0.00571 AC: 8142 AN: 1425950 Hom.: 28 Cov.: 24 AF XY: 0.00563 AC XY: 4001 AN XY: 711094

African (AFR) AF: 0.00110 AC: 36 AN: 32734

American (AMR) AF: 0.000405 AC: 18 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 34 AN: 25844

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39368

South Asian (SAS) AF: 0.000472 AC: 40 AN: 84658

European-Finnish (FIN) AF: 0.00597 AC: 310 AN: 51914

Middle Eastern (MID) AF: 0.000549 AC: 3 AN: 5466

European-Non Finnish (NFE) AF: 0.00684 AC: 7406 AN: 1082322

Other (OTH) AF: 0.00488 AC: 289 AN: 59190

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152154 Hom.: 4 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74384

African (AFR) AF: 0.00147 AC: 61 AN: 41508

American (AMR) AF: 0.000523 AC: 8 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00605 AC: 64 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00750 AC: 510 AN: 68000

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00528 Hom.: 21

Bravo AF: 0.00421

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00167 AC: 6

ESP6500EA AF: 0.00715 AC: 58

ExAC AF: 0.00536 AC: 647

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Glutaryl-CoA oxidase deficiency (5)
1	1	1	not provided (3)
1	-	-	SUGCT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.0068
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.058	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.76
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.64
ClinPred		0.031	T
GERP RS		2.5
Varity_R		0.73
gMVP		0.67
Mutation Taster		=58/42	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.010		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: rs137852860; hg19: chr7-40498796;