rs302970

Variant names:

• chr6-25128205-G-A
• rs302970
• ENST00000377993.8:n.212+9415C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.368

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]

ENSG00000285801 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMAHP	NR_002174.2	n.204+9415C>T		intron_variant	Intron 1 of 12
CMAHP	NR_027626.1	n.523+9415C>T		intron_variant	Intron 2 of 6
LOC124901282	XR_007059515.1	n.272+5673G>A		intron_variant	Intron 2 of 2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59621 AN: 151884 Hom.: 16711 Cov.: 31

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.: 31 AF XY: 0.385 AC XY: 28572 AN XY: 74308

Gnomad4 AFR AF: 0.804

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.373

Alfa AF: 0.331 Hom.: 3789

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
DANN	Benign	0.44

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs302970; hg19: chr6-25128433;