19-38605577-C-G

Variant names:

• chr19-38605577-C-G
• rs758428806
• NM_001042600.3:c.1354G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001042600.3(MAP4K1):​c.1354G>C​(p.Ala452Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,383,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A452T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MAP4K1 NM_001042600.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.56
• Publications: 0 publications found

Genes affected

MAP4K1 (HGNC:6863): (mitogen-activated protein kinase kinase kinase kinase 1) Enables ATP binding activity and MAP kinase kinase kinase kinase activity. Involved in several processes, including JNK cascade; cellular response to phorbol 13-acetate 12-myristate; and protein phosphorylation. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042600.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K1	NM_001042600.3	MANE Select	c.1354G>C	p.Ala452Pro	missense	Exon 18 of 31	NP_001036065.1	Q92918-2
	MAP4K1	NM_007181.6		c.1354G>C	p.Ala452Pro	missense	Exon 18 of 32	NP_009112.1	Q92918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K1	ENST00000396857.7	TSL:5 MANE Select	c.1354G>C	p.Ala452Pro	missense	Exon 18 of 31	ENSP00000380066.1	Q92918-2
	MAP4K1	ENST00000591517.5	TSL:1	c.1354G>C	p.Ala452Pro	missense	Exon 18 of 32	ENSP00000465039.1	Q92918-1
	MAP4K1	ENST00000864511.1		c.1474G>C	p.Ala492Pro	missense	Exon 19 of 32	ENSP00000534570.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383298 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 683444

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30618

American (AMR) AF: 0.0000340 AC: 1 AN: 29440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23818

East Asian (EAS) AF: 0.00 AC: 0 AN: 36078

South Asian (SAS) AF: 0.00 AC: 0 AN: 78294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074316

Other (OTH) AF: 0.00 AC: 0 AN: 57166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.18
Sift	Benign	0.40	T
Sift4G	Benign	0.41	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.20		Gain of glycosylation at A452 (P = 0.0317)
MVP		0.81
MPC		0.88
ClinPred		0.84	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.33
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758428806; hg19: chr19-39096217;