rs3818270

chr6-25092311-A-C

Variant summary

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

The NR_002174.2(CMAHP):n.1326-299T>G variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,044 control chromosomes in the GnomAD database, including 17,585 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 0.46 (17585 hom., cov: 32)
• Consequence: CMAHP NR_002174.2 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CMAHP	NR_002174.2	n.1326-299T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMAHP	ENST00000377993.8	n.1334-299T>G		intron_variant, non_coding_transcript_variant		1
	ENST00000643807.1	n.1690-299T>G		intron_variant, non_coding_transcript_variant
	ENST00000648291.1	n.392+13600A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70651 AN: 151926 Hom.: 17573 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.496

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

GnomAD4 genome AF: 0.465 AC: 70681 AN: 152044 Hom.: 17585 Cov.: 32 AF XY: 0.471 AC XY: 35017 AN XY: 74326

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.562

Gnomad4 SAS AF: 0.615

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.500

Alfa AF: 0.499 Hom.: 2939

Bravo AF: 0.450

Asia WGS AF: 0.582 AC: 2024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.10
Dann	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3818270; hg19: chr6-25092539;