5-218352-A-G

Variant names:

• chr5-218352-A-G
• rs377134185
• NM_004168.4:c.-4A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004168.4(SDHA):​c.-4A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,458,606 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (57 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (44 hom.)
• Consequence: SDHA NM_004168.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.05
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-218352-A-G is Benign according to our data. Variant chr5-218352-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

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.-4A>G		5_prime_UTR	Exon 1 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.-4A>G		5_prime_UTR	Exon 1 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.-4A>G		5_prime_UTR	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.-4A>G		5_prime_UTR	Exon 1 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.-4A>G		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
	ENSG00000286001	ENST00000651543.1		n.-4A>G		5_prime_UTR	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2324 AN: 152118 Hom.: 56 Cov.: 34

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00296 AC: 332 AN: 112288 AF XY: 0.00230

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.000735

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00174

GnomAD4 exome AF: 0.00148 AC: 1935 AN: 1306380 Hom.: 44 Cov.: 31 AF XY: 0.00137 AC XY: 885 AN XY: 644652

African (AFR) AF: 0.0544 AC: 1457 AN: 26784

American (AMR) AF: 0.00292 AC: 72 AN: 24684

Ashkenazi Jewish (ASJ) AF: 0.000687 AC: 14 AN: 20380

East Asian (EAS) AF: 0.0000323 AC: 1 AN: 30978

South Asian (SAS) AF: 0.000136 AC: 9 AN: 66116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33824

Middle Eastern (MID) AF: 0.00351 AC: 13 AN: 3700

European-Non Finnish (NFE) AF: 0.000161 AC: 168 AN: 1046444

Other (OTH) AF: 0.00376 AC: 201 AN: 53470

GnomAD4 genome AF: 0.0153 AC: 2332 AN: 152226 Hom.: 57 Cov.: 34 AF XY: 0.0149 AC XY: 1109 AN XY: 74428

African (AFR) AF: 0.0530 AC: 2203 AN: 41548

American (AMR) AF: 0.00516 AC: 79 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67988

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0174

Asia WGS AF: 0.00434 AC: 15 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Leigh syndrome (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.57
DANN	Benign	0.33
PhyloP100		-1.0
PromoterAI		0.011	Neutral
Mutation Taster		=300/0	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: rs377134185; hg19: chr5-218467;