dbSNP rs1054073: MCPH1:c.*435T>A (chr8-6445990-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.256

Publications

8 publications found

Variant links:

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

MCPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.1825+443T>A		intron_variant	Intron 8 of 13	ENST00000344683.10	NP_078872.3	Q8NEM0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 link	c.1825+443T>A		intron_variant	Intron 8 of 13	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.694

AC:

105472

AN:

152030

Hom.:

39447

Cov.:

show subpopulations

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.:

AF XY:

0.807

AC XY:

307703

AN XY:

381270

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

5692

11384

17075

22767

28459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.693

AC:

105507

AN:

152148

Hom.:

39457

Cov.:

AF XY:

0.702

AC XY:

52195

AN XY:

74382

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1397

2793

4190

5586

6983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

(source)

DANN

Benign

0.71

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs1054073

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over