7-40459197-C-T

Variant names:

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

Variant summary

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

• 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;