rs17570753

Positions:

• chr8-6644838-T-A
• chr8-6644838-T-C

Variant summary

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

The NM_024596.5(MCPH1):​c.*1789T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0646 in 152,076 control chromosomes in the GnomAD database, including 397 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 0.065 (397 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCPH1 NM_024596.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0190

Genes affected

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MCPH1-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.*1789T>A		3_prime_UTR_variant	14/14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.*1789T>A		3_prime_UTR_variant	14/14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 9827 AN: 151958 Hom.: 398 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0964

Gnomad FIN AF: 0.0429

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0881

Gnomad OTH AF: 0.0798

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 AFR exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0646 AC: 9831 AN: 152076 Hom.: 397 Cov.: 32 AF XY: 0.0629 AC XY: 4675 AN XY: 74340

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.0564

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0975

Gnomad4 FIN AF: 0.0429

Gnomad4 NFE AF: 0.0881

Gnomad4 OTH AF: 0.0789

Alfa AF: 0.0762 Hom.: 66

Bravo AF: 0.0642

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.96
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17570753; hg19: chr8-6502359; COSMIC: COSV60916125; COSMIC: COSV60916125;