rs764384503

Variant names:

• chr11-112086942-G-A
• rs764384503
• NM_003002.4:c.35G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-112086942-G-A
• chr11-112086942-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_003002.4(SDHD):​c.35G>A​(p.Gly12Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12S) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.99
• Publications: 1 publications found

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:):

TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 42 uncertain in NM_003002.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38305363).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003002.4. 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
	SDHD	NM_003002.4	MANE Select	c.35G>A	p.Gly12Asp	missense	Exon 1 of 4	NP_002993.1	O14521-1
	SDHD	NM_001276506.2		c.35G>A	p.Gly12Asp	missense	Exon 1 of 5	NP_001263435.1	O14521-4
	SDHD	NM_001276504.2		c.35G>A	p.Gly12Asp	missense	Exon 1 of 3	NP_001263433.1	O14521-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	ENST00000375549.8	TSL:1 MANE Select	c.35G>A	p.Gly12Asp	missense	Exon 1 of 4	ENSP00000364699.3	O14521-1
	SDHD	ENST00000528048.5	TSL:1	c.35G>A	p.Gly12Asp	missense	Exon 1 of 3	ENSP00000436217.1	O14521-3
	ENSG00000255292	ENST00000532699.1	TSL:3	n.35G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000456434.1	H3BRW5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251386 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Mitochondrial complex 2 deficiency, nuclear type 3 (1)
-	1	-	Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 (1)
-	1	-	SDHD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.0011	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.44
Sift	Benign	0.29	T
Sift4G	Benign	0.59	T
Polyphen		0.058	B
Vest4		0.54
MutPred		0.34		Gain of solvent accessibility (P = 0.024)
MVP		0.96
MPC		0.30
ClinPred		0.62	D
GERP RS		5.2
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.21
gMVP		0.59
Mutation Taster		=89/11	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: rs764384503; hg19: chr11-111957666;