dbSNP rs302970: CMAHP:n.212+9415C>T (chr6-25128205-G-A) – 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.212+9415C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,002 control chromosomes in the GnomAD database, including 16,759 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 0.39 ( 16759 hom., cov: 31)

Consequence

CMAHP
ENST00000377993.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.368

Publications

3 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=-0.95).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
CMAHP	NR_002174.2 link	n.204+9415C>T	intron_variant	Intron 1 of 12
CMAHP	NR_027626.1 link	n.523+9415C>T	intron_variant	Intron 2 of 6
LOC124901282	XR_007059515.1 link	n.272+5673G>A	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CMAHP	ENST00000377993.8 link	n.212+9415C>T	intron_variant	Intron 2 of 13	1
CMAHP	ENST00000462823.1 link	n.461-348C>T	intron_variant	Intron 2 of 2	1
CMAHP	ENST00000377989.8 link	n.724+9415C>T	intron_variant	Intron 2 of 13	2

Frequencies

GnomAD3 genomes

AF:

0.393

AC:

59621

AN:

151884

Hom.:

16711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.804

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.278

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.179

Gnomad FIN

AF:

0.200

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.378

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

GnomAD4 genome

AF:

0.393

AC:

59720

AN:

152002

Hom.:

16759

Cov.:

AF XY:

0.385

AC XY:

28572

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.804

AC:

33326

AN:

41448

American (AMR)

AF:

0.284

AC:

4340

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

966

AN:

3470

East Asian (EAS)

AF:

0.168

AC:

867

AN:

5172

South Asian (SAS)

AF:

0.179

AC:

862

AN:

4826

European-Finnish (FIN)

AF:

0.200

AC:

2115

AN:

10558

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16243

AN:

67950

Other (OTH)

AF:

0.373

AC:

787

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1334

2669

4003

5338

6672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.337

Hom.:

4794

Bravo

AF:

0.422

Asia WGS

AF:

0.203

AC:

706

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.28

(source)

DANN

Benign

0.44

PhyloP100

-0.37

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