rs150642856

Variant names:

• chr6-49444686-G-A
• rs150642856
• NM_000255.4:c.1629C>T

Variant summary

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

The NM_000255.4(MMUT):​c.1629C>T​(p.Ser543Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,613,274 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (50 hom.)
• Consequence: MMUT NM_000255.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.122
• Publications: 2 publications found

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMUT Gene-Disease associations (from GenCC):

• methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• vitamin B12-unresponsive methylmalonic acidemia type mut-

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• vitamin B12-unresponsive methylmalonic acidemia type mut0

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-49444686-G-A is Benign according to our data. Variant chr6-49444686-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92682.
• BP7: Synonymous conserved (PhyloP=0.122 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00479 (728/152118) while in subpopulation NFE AF = 0.00785 (534/67992). AF 95% confidence interval is 0.0073. There are 5 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000255.4. 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
	MMUT	NM_000255.4	MANE Select	c.1629C>T	p.Ser543Ser	synonymous	Exon 9 of 13	NP_000246.2	P22033

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	ENST00000274813.4	TSL:1 MANE Select	c.1629C>T	p.Ser543Ser	synonymous	Exon 9 of 13	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.1629C>T	p.Ser543Ser	synonymous	Exon 9 of 13	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.1629C>T	p.Ser543Ser	synonymous	Exon 9 of 13	ENSP00000548121.1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 728 AN: 152000 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00434

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00512 AC: 1286 AN: 251120 AF XY: 0.00549

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.00648 AC: 9462 AN: 1461156 Hom.: 50 Cov.: 30 AF XY: 0.00654 AC XY: 4752 AN XY: 726900

African (AFR) AF: 0.00102 AC: 34 AN: 33440

American (AMR) AF: 0.00365 AC: 163 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00786 AC: 205 AN: 26092

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00430 AC: 371 AN: 86244

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53410

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5760

European-Non Finnish (NFE) AF: 0.00732 AC: 8139 AN: 1111452

Other (OTH) AF: 0.00641 AC: 387 AN: 60364

GnomAD4 genome AF: 0.00479 AC: 728 AN: 152118 Hom.: 5 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74356

African (AFR) AF: 0.00111 AC: 46 AN: 41514

American (AMR) AF: 0.00433 AC: 66 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

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

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4814

European-Finnish (FIN) AF: 0.000850 AC: 9 AN: 10592

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00785 AC: 534 AN: 67992

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00638 Hom.: 6

Bravo AF: 0.00501

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00982

EpiControl AF: 0.0107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.8
DANN	Benign	0.51
PhyloP100		0.12
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: rs150642856; hg19: chr6-49412399;