Genetic Variant NM_024596.5:c.*5135A>T (chr8-6648184-A-T) – 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.*5135A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 152,082 control chromosomes in the GnomAD database, including 18,064 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 0.46 ( 18061 hom., cov: 32)

Exomes 𝑓: 0.42 ( 3 hom. )

Consequence

MCPH1
NM_024596.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.796

Publications

3 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=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 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	UniProt
MCPH1	NM_024596.5	MANE Select	c.*5135A>T	3_prime_UTR	Exon 14 of 14	NP_078872.3	Q8NEM0-1
MCPH1	NM_001322042.2		c.*5157A>T	3_prime_UTR	Exon 15 of 15	NP_001308971.2	A0A8I5KV10
MCPH1	NM_001363980.2		c.*5135A>T	3_prime_UTR	Exon 11 of 11	NP_001350909.1	A0A8I5KR97

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.*5135A>T	3_prime_UTR	Exon 14 of 14	ENSP00000342924.5	Q8NEM0-1
MCPH1-AS1	ENST00000749482.1		n.637T>A	non_coding_transcript_exon	Exon 1 of 2
MCPH1-AS1	ENST00000515608.5	TSL:5	n.525+99T>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.457

AC:

69376

AN:

151938

Hom.:

18018

Cov.:

show subpopulations

Gnomad AFR

AF:

0.690

Gnomad AMI

AF:

0.293

Gnomad AMR

AF:

0.501

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.685

Gnomad SAS

AF:

0.519

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.316

Gnomad OTH

AF:

0.433

GnomAD4 exome

AF:

0.423

AC:

AN:

Hom.:

Cov.:

AF XY:

0.423

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

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)

AF:

0.417

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.457

AC:

69472

AN:

152056

Hom.:

18061

Cov.:

AF XY:

0.463

AC XY:

34431

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.690

AC:

28629

AN:

41482

American (AMR)

AF:

0.502

AC:

7666

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1133

AN:

3470

East Asian (EAS)

AF:

0.685

AC:

3533

AN:

5156

South Asian (SAS)

AF:

0.519

AC:

2492

AN:

4802

European-Finnish (FIN)

AF:

0.309

AC:

3267

AN:

10582

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.316

AC:

21459

AN:

67976

Other (OTH)

AF:

0.433

AC:

914

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1744

3488

5231

6975

8719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.249

Hom.:

630

Bravo

AF:

0.479

Asia WGS

AF:

0.550

AC:

1913

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.0

(source)

DANN

Benign

0.71

PhyloP100

-0.80

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