rs1054073

Variant names:

• chr8-6445990-T-A
• rs1054073
• ENST00000519480.6:c.*435T>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000519480.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.1825+443T>A		intron	N/A	NP_078872.3
	MCPH1	NR_136159.2		n.2194T>A		non_coding_transcript_exon	Exon 7 of 7
	MCPH1	NM_001172574.2		c.*435T>A		3_prime_UTR	Exon 8 of 8	NP_001166045.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000519480.6	TSL:1	c.*435T>A		3_prime_UTR	Exon 8 of 8	ENSP00000430962.1
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.1825+443T>A		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000688099.1		n.*2547T>A		non_coding_transcript_exon	Exon 8 of 8	ENSP00000509622.1

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

African (AFR) AF: 0.349 AC: 5462 AN: 15672

American (AMR) AF: 0.834 AC: 851 AN: 1020

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 3450 AN: 5122

East Asian (EAS) AF: 0.811 AC: 2922 AN: 3602

South Asian (SAS) AF: 0.755 AC: 12291 AN: 16278

European-Finnish (FIN) AF: 0.853 AC: 261 AN: 306

Middle Eastern (MID) AF: 0.686 AC: 1096 AN: 1598

European-Non Finnish (NFE) AF: 0.819 AC: 618277 AN: 754584

Other (OTH) AF: 0.779 AC: 21077 AN: 27046

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

African (AFR) AF: 0.382 AC: 15851 AN: 41454

American (AMR) AF: 0.796 AC: 12183 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2434 AN: 3468

East Asian (EAS) AF: 0.818 AC: 4237 AN: 5178

South Asian (SAS) AF: 0.750 AC: 3623 AN: 4828

European-Finnish (FIN) AF: 0.880 AC: 9321 AN: 10592

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55406 AN: 67998

Other (OTH) AF: 0.703 AC: 1486 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.0
DANN	Benign	0.71
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1054073; hg19: chr8-6303511;