chr5-236472-G-T

Variant names:

• chr5-236472-G-T
• rs35964044
• NM_004168.4:c.1305G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004168.4(SDHA):​c.1305G>T​(p.Leu435Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,896 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L435L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 33)
  • Exomes 𝑓: 0.016 (265 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 0.0500
• Publications: 6 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]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-236472-G-T is Benign according to our data. Variant chr5-236472-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224954.
• BP7: Synonymous conserved (PhyloP=0.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0154 (2350/152354) while in subpopulation SAS AF = 0.0251 (121/4830). AF 95% confidence interval is 0.0214. There are 27 homozygotes in GnomAd4. There are 1241 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

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.1305G>T	p.Leu435Leu	synonymous	Exon 10 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.1161G>T	p.Leu387Leu	synonymous	Exon 9 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.1305G>T	p.Leu435Leu	synonymous	Exon 10 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.1305G>T	p.Leu435Leu	synonymous	Exon 10 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.*38G>T		non_coding_transcript_exon	Exon 9 of 24	ENSP00000499215.1	A0A494C1T6
	ENSG00000286001	ENST00000651543.1		n.*38G>T		3_prime_UTR	Exon 9 of 24	ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2355 AN: 152236 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0188 AC: 4729 AN: 251098 AF XY: 0.0203

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.0463

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0163 AC: 23876 AN: 1461542 Hom.: 265 Cov.: 31 AF XY: 0.0169 AC XY: 12309 AN XY: 727092

African (AFR) AF: 0.00299 AC: 100 AN: 33466

American (AMR) AF: 0.0103 AC: 461 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0466 AC: 1219 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0253 AC: 2185 AN: 86248

European-Finnish (FIN) AF: 0.0369 AC: 1971 AN: 53418

Middle Eastern (MID) AF: 0.0373 AC: 215 AN: 5760

European-Non Finnish (NFE) AF: 0.0149 AC: 16510 AN: 1111736

Other (OTH) AF: 0.0201 AC: 1213 AN: 60372

GnomAD4 genome AF: 0.0154 AC: 2350 AN: 152354 Hom.: 27 Cov.: 33 AF XY: 0.0167 AC XY: 1241 AN XY: 74500

African (AFR) AF: 0.00257 AC: 107 AN: 41586

American (AMR) AF: 0.0184 AC: 281 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4830

European-Finnish (FIN) AF: 0.0369 AC: 392 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1235 AN: 68034

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0170 Hom.: 14

Bravo AF: 0.0133

EpiCase AF: 0.0197

EpiControl AF: 0.0206

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	not provided (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	-0.55
CADD	Benign	1.6
DANN	Benign	0.46
PhyloP100		0.050
PromoterAI		-0.0048	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs35964044; hg19: chr5-236587; COSMIC: COSV53772863;