19-38605610-G-A

Position:

• chr19-38605610-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042600.3(MAP4K1):​c.1321C>T​(p.Pro441Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,413,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAP4K1 NM_001042600.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17809013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K1	NM_001042600.3	c.1321C>T	p.Pro441Ser	missense_variant	18/31	ENST00000396857.7	NP_001036065.1
MAP4K1	NM_007181.6	c.1321C>T	p.Pro441Ser	missense_variant	18/32		NP_009112.1
MAP4K1	XM_011526404.2	c.1441C>T	p.Pro481Ser	missense_variant	19/32		XP_011524706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K1	ENST00000396857.7	c.1321C>T	p.Pro441Ser	missense_variant	18/31	5	NM_001042600.3	ENSP00000380066.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1413900 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 700562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2024

The c.1321C>T (p.P441S) alteration is located in exon 18 (coding exon 18) of the MAP4K1 gene. This alteration results from a C to T substitution at nucleotide position 1321, causing the proline (P) at amino acid position 441 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.44	N
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	.;.;N
REVEL	Benign	0.035
Sift	Benign	0.29	.;.;T
Sift4G	Benign	0.97	T;T;T
Polyphen		0.19	B;.;B
Vest4		0.30
MutPred		0.30		Gain of phosphorylation at P441 (P = 4e-04);.;Gain of phosphorylation at P441 (P = 4e-04);
MVP		0.48
MPC		0.25
ClinPred		0.50	T
GERP RS		5.2
Varity_R		0.060
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr19-39096250;