NM_004168.4:c.40C>A

Variant names:

• chr5-218395-C-A
• rs1192077362
• NM_004168.4:c.40C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004168.4(SDHA):​c.40C>A​(p.Arg14Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000695 in 1,294,294 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.333
• Publications: 0 publications found

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ENSG00000286001 (HGNC:):

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-218395-C-A is Benign according to our data. Variant chr5-218395-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.333 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004168.4. 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
	SDHA	NM_004168.4	MANE Select	c.40C>A	p.Arg14Arg	synonymous	Exon 1 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.40C>A	p.Arg14Arg	synonymous	Exon 1 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.40C>A	p.Arg14Arg	synonymous	Exon 1 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.40C>A	p.Arg14Arg	synonymous	Exon 1 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.40C>A		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.40C>A	p.Arg14Arg	synonymous	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000695 AC: 9 AN: 1294294 Hom.: 0 Cov.: 31 AF XY: 0.00000626 AC XY: 4 AN XY: 638762

African (AFR) AF: 0.00 AC: 0 AN: 26524

American (AMR) AF: 0.00 AC: 0 AN: 23256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19812

East Asian (EAS) AF: 0.00 AC: 0 AN: 30796

South Asian (SAS) AF: 0.00 AC: 0 AN: 63306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3630

European-Non Finnish (NFE) AF: 0.00000865 AC: 9 AN: 1040934

Other (OTH) AF: 0.00 AC: 0 AN: 52958

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 5 (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.33
PromoterAI		0.0070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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: rs1192077362; hg19: chr5-218510;