dbSNP rs302976: CMAHP:n.213-3106G>A (chr6-25118206-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000377993.8(CMAHP):n.213-3106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,192 control chromosomes in the GnomAD database, including 6,289 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.25 ( 6289 hom., cov: 32)

Consequence

CMAHP
ENST00000377993.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.391

Publications

4 publications found

Variant links:

Genes affected

CMAHP (HGNC:2098): (cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene) Sialic acids are terminal components of the carbohydrate chains of glycoconjugates involved in ligand-receptor, cell-cell, and cell-pathogen interactions. The two most common forms of sialic acid found in mammalian cells are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative, N-glycolylneuraminic acid (Neu5Gc). Studies of sialic acid distribution show that Neu5Gc is not detectable in normal human tissues although it was an abundant sialic acid in other mammals. Neu5Gc is, in actuality, immunogenic in humans. The absense of Neu5Gc in humans is due to a deletion within the human gene CMAH encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase, an enzyme responsible for Neu5Gc biosynthesis. Sequences encoding the mouse, pig, and chimpanzee hydroxylase enzymes were obtained by cDNA cloning and found to be highly homologous. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 6 of the mouse hydroxylase gene, causes a frameshift mutation and premature termination of the polypeptide chain in human. It seems unlikely that the truncated human hydroxylase mRNA encodes for an active enzyme explaining why Neu5Gc is undetectable in normal human tissues. Human genomic DNA also shows evidence of this deletion which does not occur in the genomes of African great apes. Nonetheless, the CMAH gene maps to 6p21.32 in humans and great apes indicating that mutation of the CMAH gene occurred following human divergence from chimpanzees and bonobos. [provided by RefSeq, Jul 2008]

CMAHP links:

CMAHP (HGNC:):

CMAHP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMAHP	NR_002174.2 link	n.205-3106G>A		intron_variant	Intron 1 of 12
CMAHP	NR_027626.1 link	n.524-3106G>A		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CMAHP	ENST00000377993.8 link	n.213-3106G>A	intron_variant	Intron 2 of 13	1
CMAHP	ENST00000377989.8 link	n.725-3106G>A	intron_variant	Intron 2 of 13	2
CMAHP	ENST00000458373.6 link	n.471-3106G>A	intron_variant	Intron 2 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.248

AC:

37720

AN:

152074

Hom.:

6270

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.0725

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.240

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.248

AC:

37782

AN:

152192

Hom.:

6289

Cov.:

AF XY:

0.244

AC XY:

18138

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.479

AC:

19889

AN:

41484

American (AMR)

AF:

0.203

AC:

3100

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

513

AN:

3468

East Asian (EAS)

AF:

0.147

AC:

759

AN:

5176

South Asian (SAS)

AF:

0.128

AC:

619

AN:

4834

European-Finnish (FIN)

AF:

0.111

AC:

1180

AN:

10612

Middle Eastern (MID)

AF:

0.202

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.163

AC:

11095

AN:

68018

Other (OTH)

AF:

0.238

AC:

502

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1321

2642

3962

5283

6604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.226

Hom.:

669

Bravo

AF:

0.268

Asia WGS

AF:

0.153

AC:

532

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

2.4

(source)

DANN

Benign

0.64

PhyloP100

-0.39

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over