rs899706404

Variant names:

• chr11-112087944-A-C
• NM_003002.4:c.140A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-112087944-A-C
• chr11-112087944-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003002.4(SDHD):​c.140A>C​(p.Gln47Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

ENSG00000255292 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.140A>C	p.Gln47Pro	missense_variant	Exon 2 of 4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.140A>C	p.Gln47Pro	missense_variant	Exon 2 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.140A>C		non_coding_transcript_exon_variant	Exon 2 of 6	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q47P variant (also known as c.140A>C), located in coding exon 2 of the SDHD gene, results from an A to C substitution at nucleotide position 140. The glutamine at codon 47 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;.
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.0	M;M;.;M;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.42	N;.;N;D;N;N
REVEL	Pathogenic	0.74
Sift	Benign	0.047	D;.;D;D;T;T
Sift4G	Benign	0.25	T;T;T;D;T;T
Polyphen		0.93	P;.;.;.;.;.
Vest4		0.77
MutPred		0.55		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.99
MPC		0.56
ClinPred		0.70	D
GERP RS		3.8
Varity_R		0.13
gMVP		0.83

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: chr11-111958668;