ENST00000377993.8:n.1149G>C

Variant names:

• chr6-25097070-C-G
• rs1128827
• ENST00000377993.8:n.1149G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000377993.8(CMAHP):​n.1149G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 468,096 control chromosomes in the GnomAD database, including 1,965 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 0.10 (1060 hom., cov: 32)
  • Exomes 𝑓: 0.068 (905 hom.)
• Consequence: CMAHP ENST00000377993.8 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• Publications: 7 publications found

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 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.151).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMAHP	NR_002174.2	n.1141G>C		non_coding_transcript_exon_variant	Exon 8 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMAHP	ENST00000377993.8	n.1149G>C		non_coding_transcript_exon_variant	Exon 9 of 14	1
CMAHP	ENST00000377989.8	n.1661G>C		non_coding_transcript_exon_variant	Exon 9 of 14	2
CMAHP	ENST00000490939.1	n.375G>C		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15765 AN: 152086 Hom.: 1053 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0624

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0283

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0692

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.0688 AC: 10279 AN: 149444 AF XY: 0.0678

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.0397

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0287

Gnomad FIN exome AF: 0.0828

Gnomad NFE exome AF: 0.0689

Gnomad OTH exome AF: 0.0674

GnomAD4 exome AF: 0.0677 AC: 21379 AN: 315892 Hom.: 905 Cov.: 0 AF XY: 0.0665 AC XY: 11878 AN XY: 178566

African (AFR) AF: 0.190 AC: 1608 AN: 8470

American (AMR) AF: 0.0402 AC: 1071 AN: 26668

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 1170 AN: 10672

East Asian (EAS) AF: 0.0293 AC: 270 AN: 9200

South Asian (SAS) AF: 0.0531 AC: 3125 AN: 58860

European-Finnish (FIN) AF: 0.0816 AC: 2206 AN: 27022

Middle Eastern (MID) AF: 0.0536 AC: 149 AN: 2778

European-Non Finnish (NFE) AF: 0.0677 AC: 10705 AN: 158022

Other (OTH) AF: 0.0757 AC: 1075 AN: 14200

GnomAD4 genome AF: 0.104 AC: 15796 AN: 152204 Hom.: 1060 Cov.: 32 AF XY: 0.102 AC XY: 7572 AN XY: 74430

African (AFR) AF: 0.197 AC: 8154 AN: 41488

American (AMR) AF: 0.0624 AC: 955 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 392 AN: 3468

East Asian (EAS) AF: 0.0283 AC: 147 AN: 5188

South Asian (SAS) AF: 0.0472 AC: 228 AN: 4826

European-Finnish (FIN) AF: 0.0879 AC: 931 AN: 10590

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0692 AC: 4705 AN: 68018

Other (OTH) AF: 0.0974 AC: 206 AN: 2114

Alfa AF: 0.0640 Hom.: 121

Bravo AF: 0.106

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.24
PhyloP100		3.2

Splicing

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

Other links and lift over

dbSNP: rs1128827; hg19: chr6-25097298;