rs1054073

Positions:

• chr8-6445990-T-A
• chr8-6445990-T-C
• chr8-6445990-T-G

Variant summary

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

The ENST00000519480.6(MCPH1):​c.*435T>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 0.789 in 977,376 control chromosomes in the GnomAD database, including 309,827 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 0.69 (39457 hom., cov: 33)
  • Exomes 𝑓: 0.81 (270370 hom.)
• Consequence: MCPH1 ENST00000519480.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.256

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.1825+443T>A		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.1825+443T>A		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105472 AN: 152030 Hom.: 39447 Cov.: 33

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.701

GnomAD4 exome AF: 0.807 AC: 665687 AN: 825228 Hom.: 270370 Cov.: 18 AF XY: 0.807 AC XY: 307703 AN XY: 381270

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.834

Gnomad4 ASJ exome AF: 0.674

Gnomad4 EAS exome AF: 0.811

Gnomad4 SAS exome AF: 0.755

Gnomad4 FIN exome AF: 0.853

Gnomad4 NFE exome AF: 0.819

Gnomad4 OTH exome AF: 0.779

GnomAD4 genome AF: 0.693 AC: 105507 AN: 152148 Hom.: 39457 Cov.: 33 AF XY: 0.702 AC XY: 52195 AN XY: 74382

Gnomad4 AFR AF: 0.382

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.818

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.880

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.703

Alfa AF: 0.683 Hom.: 2448

Bravo AF: 0.675

Asia WGS AF: 0.766 AC: 2658 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.0
DANN	Benign	0.71

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: rs1054073; hg19: chr8-6303511;