8-6406674-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_024596.5(MCPH1):c.7G>T(p.Ala3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.520

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-DT (HGNC:55599): (MCPH1 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain BRCT 1 (size 92) in uniprot entity MCPH1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_024596.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08617422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.7G>T	p.Ala3Ser	missense_variant	1/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.7G>T	p.Ala3Ser	missense_variant	1/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1349440). This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3 of the MCPH1 protein (p.Ala3Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	13
Dann	Uncertain	1.0
DEOGEN2	Benign	0.073	T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.45	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.025	D;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.010	B;.;.
Vest4		0.15
MutPred		0.26		Gain of disorder (P = 0.0412);Gain of disorder (P = 0.0412);Gain of disorder (P = 0.0412);
MVP		0.27
ClinPred		0.60	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-6264195;