19-38601519-C-T

Variant names:

• chr19-38601519-C-T
• rs780188843
• NM_001042600.3:c.1453G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042600.3(MAP4K1):​c.1453G>A​(p.Ala485Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A485S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAP4K1 NM_001042600.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.141
• 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]

MAP4K1-AS1 (HGNC:55302): (MAP4K1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19152898).

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.1453G>A	p.Ala485Thr	missense	Exon 20 of 31	NP_001036065.1	Q92918-2
	MAP4K1	NM_007181.6		c.1453G>A	p.Ala485Thr	missense	Exon 20 of 32	NP_009112.1	Q92918-1
	MAP4K1-AS1	NR_134907.1		n.340C>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K1	ENST00000396857.7	TSL:5 MANE Select	c.1453G>A	p.Ala485Thr	missense	Exon 20 of 31	ENSP00000380066.1	Q92918-2
	MAP4K1	ENST00000591517.5	TSL:1	c.1453G>A	p.Ala485Thr	missense	Exon 20 of 32	ENSP00000465039.1	Q92918-1
	MAP4K1	ENST00000864511.1		c.1573G>A	p.Ala525Thr	missense	Exon 21 of 32	ENSP00000534570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454290 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722586

⚠️ 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: 33342

American (AMR) AF: 0.00 AC: 0 AN: 43720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108854

Other (OTH) AF: 0.00 AC: 0 AN: 60132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000096912), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.14
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.031
Sift	Benign	0.038	D
Sift4G	Uncertain	0.025	D
Polyphen		0.0040	B
Vest4		0.16
MutPred		0.58		Loss of sheet (P = 0.0817)
MVP		0.74
MPC		0.20
ClinPred		0.59	D
GERP RS		2.8
Varity_R		0.062
gMVP		0.43
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs780188843; hg19: chr19-39092159; COSMIC: COSV101204300; COSMIC: COSV101204300;