Genetic Variant NM_001193313.2:c.985C>G (chr7-40459197-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001193313.2(SUGCT):c.985C>G(p.Arg329Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,210 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R329W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SUGCT
NM_001193313.2 missense, splice_region

Scores

Splicing: ADA: 0.0006346

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.756

Publications

0 publications found

Variant links:

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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

SUGCT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUGCT	NM_001193313.2 link	c.985C>G	p.Arg329Gly	missense_variant, splice_region_variant	Exon 11 of 14	ENST00000335693.9	NP_001180242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SUGCT	ENST00000335693.9 link	c.985C>G	p.Arg329Gly	missense_variant, splice_region_variant	Exon 11 of 14	1	NM_001193313.2	ENSP00000338475.5
SUGCT	ENST00000628514.3 link	c.985C>G	p.Arg329Gly	missense_variant, splice_region_variant	Exon 11 of 15	1		ENSP00000486291.2
SUGCT	ENST00000416370.2 link	c.985C>G	p.Arg329Gly	missense_variant, splice_region_variant	Exon 11 of 13	1		ENSP00000393032.2
SUGCT	ENST00000401647.7 link	c.841C>G	p.Arg281Gly	missense_variant, splice_region_variant	Exon 10 of 13	1		ENSP00000385222.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1426210

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711204

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32734

American (AMR)

AF:

0.00

AC:

AN:

44454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25852

East Asian (EAS)

AF:

0.00

AC:

AN:

39368

South Asian (SAS)

AF:

0.00

AC:

AN:

84658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5466

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1082570

Other (OTH)

AF:

0.00

AC:

AN:

59192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;T

Eigen

Benign

-0.095

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.86

D;D;D

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.6

.;M;M

PhyloP100

0.76

PROVEAN

Uncertain

-3.2

D;.;D

REVEL

Uncertain

0.54

Sift

Benign

0.032

D;.;D

Sift4G

Benign

0.16

T;T;T

Polyphen

0.95

.;.;P

Vest4

0.72

MutPred

0.55

.;Loss of stability (P = 0.025);Loss of stability (P = 0.025);

MVP

0.68

ClinPred

0.97

GERP RS

2.5

Varity_R

0.84

gMVP

0.66

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00063

dbscSNV1_RF

Benign

0.020

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over