19-38593306-G-A

Position:

• chr19-38593306-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001042600.3(MAP4K1):​c.2372C>T​(p.Thr791Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAP4K1 NM_001042600.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

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]

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29608452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K1	NM_001042600.3	c.2372C>T	p.Thr791Ile	missense_variant	30/31	ENST00000396857.7
MAP4K1	NM_007181.6	c.2372C>T	p.Thr791Ile	missense_variant	30/32
MAP4K1	XM_011526404.2	c.2492C>T	p.Thr831Ile	missense_variant	31/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP4K1	ENST00000396857.7	c.2372C>T	p.Thr791Ile	missense_variant	30/31	5	NM_001042600.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460166 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726306

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

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 18, 2023

The c.2372C>T (p.T791I) alteration is located in exon 30 (coding exon 30) of the MAP4K1 gene. This alteration results from a C to T substitution at nucleotide position 2372, causing the threonine (T) at amino acid position 791 to be replaced by an isoleucine (I). 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	0.19
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.81
DEOGEN2	Benign	0.042	T;T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N;.;.;N
MutationTaster	Benign	0.82	D;D;D;N
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	0.88	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.63
MutPred		0.45		Loss of phosphorylation at T791 (P = 0.079);.;.;Loss of phosphorylation at T791 (P = 0.079);
MVP		0.77
MPC		2.5
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.096
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs759150067; hg19: chr19-39083946;