chr4-145651075-G-A

Variant names:

• chr4-145651075-G-A
• rs11721553
• NM_172250.3:c.747G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_172250.3(MMAA):​c.747G>A​(p.Ser249Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0894 in 1,613,392 control chromosomes in the GnomAD database, including 7,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (538 hom., cov: 32)
  • Exomes 𝑓: 0.091 (6705 hom.)
• Consequence: MMAA NM_172250.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.51
• Publications: 8 publications found

Genes affected

MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMAA Gene-Disease associations (from GenCC):

• methylmalonic aciduria, cblA type

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 4-145651075-G-A is Benign according to our data. Variant chr4-145651075-G-A is described in ClinVar as Benign. ClinVar VariationId is 138237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172250.3. 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
	MMAA	NM_172250.3	MANE Select	c.747G>A	p.Ser249Ser	synonymous	Exon 5 of 7	NP_758454.1
	MMAA	NM_001375644.1		c.747G>A	p.Ser249Ser	synonymous	Exon 5 of 7	NP_001362573.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAA	ENST00000649156.2	MANE Select	c.747G>A	p.Ser249Ser	synonymous	Exon 5 of 7	ENSP00000497008.1
	MMAA	ENST00000511969.4	TSL:1	n.734-2919G>A		intron	N/A	ENSP00000427422.1
	MMAA	ENST00000541599.5	TSL:5	c.747G>A	p.Ser249Ser	synonymous	Exon 5 of 7	ENSP00000442284.3

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11664 AN: 152130 Hom.: 537 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.00731

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0908

GnomAD2 exomes AF: 0.0707 AC: 17765 AN: 251448 AF XY: 0.0712

Gnomad AFR exome AF: 0.0596

Gnomad AMR exome AF: 0.0515

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.00772

Gnomad FIN exome AF: 0.0395

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0907 AC: 132523 AN: 1461144 Hom.: 6705 Cov.: 31 AF XY: 0.0890 AC XY: 64665 AN XY: 726950

African (AFR) AF: 0.0585 AC: 1960 AN: 33476

American (AMR) AF: 0.0544 AC: 2431 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 1725 AN: 26132

East Asian (EAS) AF: 0.00504 AC: 200 AN: 39694

South Asian (SAS) AF: 0.0358 AC: 3091 AN: 86254

European-Finnish (FIN) AF: 0.0408 AC: 2180 AN: 53404

Middle Eastern (MID) AF: 0.0882 AC: 509 AN: 5768

European-Non Finnish (NFE) AF: 0.103 AC: 115016 AN: 1111326

Other (OTH) AF: 0.0896 AC: 5411 AN: 60368

GnomAD4 genome AF: 0.0766 AC: 11668 AN: 152248 Hom.: 538 Cov.: 32 AF XY: 0.0714 AC XY: 5311 AN XY: 74434

African (AFR) AF: 0.0608 AC: 2528 AN: 41550

American (AMR) AF: 0.0691 AC: 1057 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.00713 AC: 37 AN: 5186

South Asian (SAS) AF: 0.0376 AC: 181 AN: 4820

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10602

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6954 AN: 67998

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.0931 Hom.: 707

Bravo AF: 0.0804

Asia WGS AF: 0.0550 AC: 193 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.109

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Methylmalonic aciduria, cblA type (6)
-	-	4	not specified (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.3
DANN	Benign	0.71
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs11721553; hg19: chr4-146572227; COSMIC: COSV55580116; COSMIC: COSV55580116;