rs121908984

Variant names:

• chr11-112094923-C-A
• rs121908984
• NM_003002.4:c.433C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-112094923-C-A
• chr11-112094923-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP4

The NM_003002.4(SDHD):​c.433C>A​(p.His145Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,458,918 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. H145Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.96
• Publications: 4 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]

SDHD Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 uncertain in NM_003002.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.41076955).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	NM_003002.4	MANE Select	c.433C>A	p.His145Asn	missense	Exon 4 of 4	NP_002993.1
	SDHD	NM_001276504.2		c.316C>A	p.His106Asn	missense	Exon 3 of 3	NP_001263433.1
	SDHD	NR_077060.2		n.522C>A		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	ENST00000375549.8	TSL:1 MANE Select	c.433C>A	p.His145Asn	missense	Exon 4 of 4	ENSP00000364699.3
	SDHD	ENST00000528048.5	TSL:1	c.*30C>A		3_prime_UTR	Exon 3 of 3	ENSP00000436217.1
	ENSG00000255292	ENST00000532699.1	TSL:3	n.314+5912C>A		intron	N/A	ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248184 AF XY: 0.0000148

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1458918 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 725798

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111096

Other (OTH) AF: 0.00 AC: 0 AN: 60180

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cowden syndrome 3 (1)
-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.15
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	-0.41	N
PhyloP100		2.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.49
Sift	Benign	0.63	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.70
MutPred		0.81		Loss of stability (P = 0.1124)
MVP		0.84
MPC		0.21
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.085
gMVP		0.86
Mutation Taster		=28/72	disease causing

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: rs121908984; hg19: chr11-111965647;