2-101790717-C-T

Variant names:

• chr2-101790717-C-T
• rs373459163
• NM_001395002.1:c.124-3C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001395002.1(MAP4K4):​c.124-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,606,880 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MAP4K4 NM_001395002.1 splice_region, intron
• Scores: Splicing: ADA: 0.1837
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.87

Genes affected

MAP4K4 (HGNC:6866): (mitogen-activated protein kinase kinase kinase kinase 4) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-101790717-C-T is Benign according to our data. Variant chr2-101790717-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 514744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP4K4	NM_001395002.1	c.124-3C>T		splice_region_variant, intron_variant	Intron 2 of 32	ENST00000324219.9	NP_001381931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP4K4	ENST00000324219.9	c.124-3C>T		splice_region_variant, intron_variant	Intron 2 of 32	5	NM_001395002.1	ENSP00000313644.6

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000166 AC: 40 AN: 240354 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000298

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1454734 Hom.: 1 Cov.: 29 AF XY: 0.000148 AC XY: 107 AN XY: 722998

Gnomad4 AFR exome AF: 0.0000899 AC: 3 AN: 33370

Gnomad4 AMR exome AF: 0.000296 AC: 13 AN: 43926

Gnomad4 ASJ exome AF: 0.000348 AC: 9 AN: 25896

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39564

Gnomad4 SAS exome AF: 0.000188 AC: 16 AN: 84956

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53078

Gnomad4 NFE exome AF: 0.0000993 AC: 110 AN: 1108032

Gnomad4 Remaining exome AF: 0.000532 AC: 32 AN: 60152

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74392

Gnomad4 AFR AF: 0.0000482 AC: 0.0000481788 AN: 0.0000481788

Gnomad4 AMR AF: 0.000720 AC: 0.000720084 AN: 0.000720084

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000415 AC: 0.000414766 AN: 0.000414766

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000206 AC: 0.000205901 AN: 0.000205901

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000234

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.14
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: rs373459163; hg19: chr2-102407179;