rs12817689

Variant names:

• chr12-109554193-A-G
• rs12817689
• NM_052845.4:c.*2835T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-109554193-A-G
• chr12-109554193-A-C
• chr12-109554193-A-T

Variant summary

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

The NM_052845.4(MMAB):​c.*2835T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 453,124 control chromosomes in the GnomAD database, including 6,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2260 hom., cov: 32)
  • Exomes 𝑓: 0.16 (4199 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.523
• Publications: 14 publications found

Genes affected

MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

MMAB Gene-Disease associations (from GenCC):

• methylmalonic acidemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• methylmalonic aciduria, cblB type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-109554193-A-G is Benign according to our data. Variant chr12-109554193-A-G is described in ClinVar as Benign. ClinVar VariationId is 307007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052845.4. 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
	MMAB	NM_052845.4	MANE Select	c.*2835T>C		3_prime_UTR	Exon 9 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.3699T>C		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.*2835T>C		3_prime_UTR	Exon 9 of 9	ENSP00000445920.1	Q96EY8

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25771 AN: 152010 Hom.: 2263 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0989

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.162 AC: 21111 AN: 130236 AF XY: 0.162

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.163 AC: 49028 AN: 300996 Hom.: 4199 Cov.: 0 AF XY: 0.160 AC XY: 27454 AN XY: 171388

African (AFR) AF: 0.184 AC: 1574 AN: 8536

American (AMR) AF: 0.147 AC: 4007 AN: 27266

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 2028 AN: 10768

East Asian (EAS) AF: 0.147 AC: 1356 AN: 9196

South Asian (SAS) AF: 0.138 AC: 8223 AN: 59638

European-Finnish (FIN) AF: 0.112 AC: 1389 AN: 12364

Middle Eastern (MID) AF: 0.194 AC: 223 AN: 1148

European-Non Finnish (NFE) AF: 0.176 AC: 27873 AN: 158076

Other (OTH) AF: 0.168 AC: 2355 AN: 14004

GnomAD4 genome AF: 0.169 AC: 25781 AN: 152128 Hom.: 2260 Cov.: 32 AF XY: 0.164 AC XY: 12203 AN XY: 74362

African (AFR) AF: 0.189 AC: 7835 AN: 41490

American (AMR) AF: 0.156 AC: 2384 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3466

East Asian (EAS) AF: 0.140 AC: 723 AN: 5168

South Asian (SAS) AF: 0.130 AC: 627 AN: 4826

European-Finnish (FIN) AF: 0.0989 AC: 1049 AN: 10602

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11887 AN: 67994

Other (OTH) AF: 0.175 AC: 369 AN: 2106

Alfa AF: 0.177 Hom.: 744

Bravo AF: 0.176

Asia WGS AF: 0.153 AC: 531 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Methylmalonic aciduria, cblB type (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.62
PhyloP100		0.52
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: rs12817689; hg19: chr12-109991998;