NM_003002.4:c.*428A>G

Variant names:

• chr11-112095398-A-G
• rs184654032
• NM_003002.4:c.*428A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003002.4(SDHD):​c.*428A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 291,614 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (6 hom.)
• Consequence: SDHD NM_003002.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.241
• 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]

SDHD Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

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

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Ambry Genetics
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 11-112095398-A-G is Benign according to our data. Variant chr11-112095398-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00587 (894/152348) while in subpopulation NFE AF = 0.00814 (554/68032). AF 95% confidence interval is 0.00758. There are 3 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.*428A>G		3_prime_UTR	Exon 4 of 4	NP_002993.1	O14521-1
	SDHD	NM_001276506.2		c.*606A>G		3_prime_UTR	Exon 5 of 5	NP_001263435.1	O14521-4
	SDHD	NM_001276504.2		c.*428A>G		3_prime_UTR	Exon 3 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.*428A>G		3_prime_UTR	Exon 4 of 4	ENSP00000364699.3	O14521-1
	SDHD	ENST00000528048.5	TSL:1	c.*505A>G		3_prime_UTR	Exon 3 of 3	ENSP00000436217.1	O14521-3
	ENSG00000255292	ENST00000532699.1	TSL:3	n.314+6387A>G		intron	N/A	ENSP00000456434.1	H3BRW5

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 895 AN: 152230 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00970

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00814

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00619 AC: 862 AN: 139266 Hom.: 6 Cov.: 0 AF XY: 0.00616 AC XY: 419 AN XY: 68040

African (AFR) AF: 0.00167 AC: 9 AN: 5398

American (AMR) AF: 0.00790 AC: 49 AN: 6202

Ashkenazi Jewish (ASJ) AF: 0.000787 AC: 5 AN: 6350

East Asian (EAS) AF: 0.00 AC: 0 AN: 14590

South Asian (SAS) AF: 0.00555 AC: 52 AN: 9362

European-Finnish (FIN) AF: 0.00545 AC: 14 AN: 2570

Middle Eastern (MID) AF: 0.00449 AC: 3 AN: 668

European-Non Finnish (NFE) AF: 0.00781 AC: 660 AN: 84536

Other (OTH) AF: 0.00730 AC: 70 AN: 9590

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152348 Hom.: 3 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74488

African (AFR) AF: 0.00159 AC: 66 AN: 41590

American (AMR) AF: 0.00785 AC: 120 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4826

European-Finnish (FIN) AF: 0.00970 AC: 103 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00814 AC: 554 AN: 68032

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00974 Hom.: 2

Bravo AF: 0.00490

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.3
DANN	Benign	0.81
PhyloP100		0.24
Mutation Taster		=100/0	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: rs184654032; hg19: chr11-111966122;