Genetic Variant MCPH1:c.*1789T>A (chr8-6644838-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 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0190

Publications

6 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 links:

MCPH1-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

MCPH1-AS1 links:

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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=-0.79).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0903 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCPH1	NM_024596.5	MANE Select	c.*1789T>A	3_prime_UTR	Exon 14 of 14	NP_078872.3
MCPH1	NM_001322042.2		c.*1811T>A	3_prime_UTR	Exon 15 of 15	NP_001308971.2
MCPH1	NM_001363980.2		c.*1789T>A	3_prime_UTR	Exon 11 of 11	NP_001350909.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.*1789T>A	3_prime_UTR	Exon 14 of 14	ENSP00000342924.5
MCPH1-AS1	ENST00000515608.5	TSL:5	n.525+3445A>T	intron	N/A
MCPH1-AS1	ENST00000522897.1	TSL:4	n.61-17528A>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0647

AC:

9827

AN:

151958

Hom.:

398

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.0646

AC:

9831

AN:

152076

Hom.:

397

Cov.:

AF XY:

0.0629

AC XY:

4675

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0327

AC:

1355

AN:

41486

American (AMR)

AF:

0.0564

AC:

861

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

428

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5178

South Asian (SAS)

AF:

0.0975

AC:

469

AN:

4808

European-Finnish (FIN)

AF:

0.0429

AC:

454

AN:

10572

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0881

AC:

5991

AN:

67966

Other (OTH)

AF:

0.0789

AC:

167

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

466

932

1398

1864

2330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0762

Hom.:

Bravo

AF:

0.0642

Asia WGS

AF:

0.0470

AC:

163

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.96

(source)

DANN

Benign

0.76

PhyloP100

-0.019

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over