6-49441774-G-C

Variant names:

• chr6-49441774-G-C
• rs9473555
• NM_000255.4:c.1808+66C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000255.4(MMUT):​c.1808+66C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,514,896 control chromosomes in the GnomAD database, including 99,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (9680 hom., cov: 31)
  • Exomes 𝑓: 0.36 (89875 hom.)
• Consequence: MMUT NM_000255.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.462
• Publications: 20 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: ClinGen, Labcorp Genetics (formerly Invitae), 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=-0.89).
• BP6: Variant 6-49441774-G-C is Benign according to our data. Variant chr6-49441774-G-C is described in ClinVar as Benign. ClinVar VariationId is 1248555.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.1808+66C>G		intron_variant	Intron 10 of 12	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.1808+66C>G		intron_variant	Intron 10 of 12		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.1808+66C>G		intron_variant	Intron 10 of 12	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53465 AN: 150658 Hom.: 9667 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.359 AC: 490399 AN: 1364142 Hom.: 89875 AF XY: 0.359 AC XY: 242897 AN XY: 677342

African (AFR) AF: 0.381 AC: 11636 AN: 30566

American (AMR) AF: 0.195 AC: 7578 AN: 38794

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 7804 AN: 23802

East Asian (EAS) AF: 0.227 AC: 8051 AN: 35538

South Asian (SAS) AF: 0.353 AC: 24995 AN: 70732

European-Finnish (FIN) AF: 0.367 AC: 17718 AN: 48284

Middle Eastern (MID) AF: 0.262 AC: 1420 AN: 5424

European-Non Finnish (NFE) AF: 0.371 AC: 392031 AN: 1055490

Other (OTH) AF: 0.345 AC: 19166 AN: 55512

GnomAD4 genome AF: 0.355 AC: 53507 AN: 150754 Hom.: 9680 Cov.: 31 AF XY: 0.351 AC XY: 25875 AN XY: 73638

African (AFR) AF: 0.385 AC: 15892 AN: 41264

American (AMR) AF: 0.254 AC: 3843 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1209 AN: 3466

East Asian (EAS) AF: 0.218 AC: 1126 AN: 5162

South Asian (SAS) AF: 0.371 AC: 1777 AN: 4786

European-Finnish (FIN) AF: 0.368 AC: 3706 AN: 10064

Middle Eastern (MID) AF: 0.217 AC: 63 AN: 290

European-Non Finnish (NFE) AF: 0.369 AC: 24920 AN: 67612

Other (OTH) AF: 0.327 AC: 679 AN: 2076

Alfa AF: 0.242 Hom.: 594

Bravo AF: 0.343

Asia WGS AF: 0.339 AC: 1182 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs9473555; hg19: chr6-49409487; COSMIC: COSV51272685;