14-50434571-G-C

Position:

• chr14-50434571-G-C

Variant summary

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

The NM_006575.6(MAP4K5):​c.1987C>G​(p.His663Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP4K5 NM_006575.6 missense, splice_region
• Scores: Splicing: ADA: 0.8365
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

Genes affected

MAP4K5 (HGNC:6867): (mitogen-activated protein kinase kinase kinase kinase 5) This gene encodes a member of the serine/threonine protein kinase family, that is highly similar to yeast SPS1/STE20 kinase. Yeast SPS1/STE20 functions near the beginning of the MAP kinase signal cascades that is essential for yeast pheromone response. This kinase was shown to activate Jun kinase in mammalian cells, which suggested a role in stress response. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K5	NM_006575.6	c.1987C>G	p.His663Asp	missense_variant, splice_region_variant	28/33	ENST00000682126.1	NP_006566.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K5	ENST00000682126.1	c.1987C>G	p.His663Asp	missense_variant, splice_region_variant	28/33		NM_006575.6	ENSP00000507200	P1
MAP4K5	ENST00000013125.9	c.1987C>G	p.His663Asp	missense_variant, splice_region_variant	28/33	1		ENSP00000013125	P1
MAP4K5	ENST00000554990.6	n.2740C>G		splice_region_variant, non_coding_transcript_exon_variant	14/19	2
MAP4K5	ENST00000557390.6	c.1987C>G	p.His663Asp	missense_variant, splice_region_variant, NMD_transcript_variant	28/33	3		ENSP00000451980

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 06, 2023

The c.1987C>G (p.H663D) alteration is located in exon 28 (coding exon 27) of the MAP4K5 gene. This alteration results from a C to G substitution at nucleotide position 1987, causing the histidine (H) at amino acid position 663 to be replaced by an aspartic acid (D). 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	Uncertain	0.54
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.23
Sift	Uncertain	0.016	D
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.60
MutPred		0.66		Gain of catalytic residue at L668 (P = 0.0155);
MVP		0.44
MPC		0.47
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.58
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: chr14-50901289;