rs34886916

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015702.3(MMADHC):​c.428G>T​(p.Ser143Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,632 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 30 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

MMADHC
NM_015702.3 missense

Scores

4
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.533
Variant links:
Genes affected
MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0064358115).
BP6
Variant 2-149576487-C-A is Benign according to our data. Variant chr2-149576487-C-A is described in ClinVar as [Benign]. Clinvar id is 331379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-149576487-C-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00982 (1495/152288) while in subpopulation AFR AF= 0.0339 (1411/41566). AF 95% confidence interval is 0.0325. There are 30 homozygotes in gnomad4. There are 705 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MMADHCNM_015702.3 linkuse as main transcriptc.428G>T p.Ser143Ile missense_variant 5/8 ENST00000303319.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MMADHCENST00000303319.10 linkuse as main transcriptc.428G>T p.Ser143Ile missense_variant 5/81 NM_015702.3 P1
MMADHCENST00000422782.2 linkuse as main transcriptc.428G>T p.Ser143Ile missense_variant 5/95
MMADHCENST00000428879.5 linkuse as main transcriptc.428G>T p.Ser143Ile missense_variant 4/72 P1

Frequencies

GnomAD3 genomes
AF:
0.00978
AC:
1488
AN:
152170
Hom.:
30
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0339
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00334
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.0110
GnomAD3 exomes
AF:
0.00259
AC:
651
AN:
251344
Hom.:
17
AF XY:
0.00196
AC XY:
266
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.0349
Gnomad AMR exome
AF:
0.00179
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.00108
AC:
1574
AN:
1461344
Hom.:
29
Cov.:
33
AF XY:
0.000916
AC XY:
666
AN XY:
726994
show subpopulations
Gnomad4 AFR exome
AF:
0.0369
Gnomad4 AMR exome
AF:
0.00201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000828
Gnomad4 OTH exome
AF:
0.00222
GnomAD4 genome
AF:
0.00982
AC:
1495
AN:
152288
Hom.:
30
Cov.:
33
AF XY:
0.00947
AC XY:
705
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0339
Gnomad4 AMR
AF:
0.00333
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.0109
Alfa
AF:
0.00360
Hom.:
3
Bravo
AF:
0.0112
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.0338
AC:
149
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00316
AC:
384
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxApr 03, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Disorders of Intracellular Cobalamin Metabolism Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
T;T;T
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.019
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
.;D;D
MetaRNN
Benign
0.0064
T;T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
1.4
L;L;.
MutationTaster
Benign
0.96
N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-2.1
N;N;N
REVEL
Benign
0.23
Sift
Uncertain
0.026
D;D;T
Sift4G
Benign
0.19
T;T;T
Polyphen
0.24
B;B;P
Vest4
0.40
MVP
0.75
MPC
0.040
ClinPred
0.037
T
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.28

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34886916; hg19: chr2-150433001; API