19-38596446-G-C

Position:

• chr19-38596446-G-C

Variant summary

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

The NM_001042600.3(MAP4K1):​c.1982C>G​(p.Ala661Gly) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP4K1 NM_001042600.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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

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=0.2456831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K1	NM_001042600.3	c.1982C>G	p.Ala661Gly	missense_variant	26/31	ENST00000396857.7	NP_001036065.1
MAP4K1-AS1	NR_134907.1	n.90+10G>C		intron_variant, non_coding_transcript_variant
MAP4K1	NM_007181.6	c.1982C>G	p.Ala661Gly	missense_variant	26/32		NP_009112.1
MAP4K1	XM_011526404.2	c.2102C>G	p.Ala701Gly	missense_variant	27/32		XP_011524706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K1	ENST00000396857.7	c.1982C>G	p.Ala661Gly	missense_variant	26/31	5	NM_001042600.3	ENSP00000380066	P1
MAP4K1-AS1	ENST00000589557.1	n.91+10G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Mar 16, 2022

The c.1982C>G (p.A661G) alteration is located in exon 26 (coding exon 26) of the MAP4K1 gene. This alteration results from a C to G substitution at nucleotide position 1982, causing the alanine (A) at amino acid position 661 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T;T;.
Eigen	Benign	-0.071
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.56	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	.;.;N
REVEL	Benign	0.092
Sift	Uncertain	0.0050	.;.;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		0.20	B;.;B
Vest4		0.22
MutPred		0.81		Loss of sheet (P = 0.0228);.;Loss of sheet (P = 0.0228);
MVP		0.46
MPC		1.6
ClinPred		0.66	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.36

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: chr19-39087086;