rs13430711

Variant names:

• chr2-101697975-T-C
• rs13430711
• NM_001395002.1:c.-106T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-101697975-T-C
• chr2-101697975-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395002.1(MAP4K4):​c.-106T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 694,944 control chromosomes in the GnomAD database, including 173,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42272 hom., cov: 33)
  • Exomes 𝑓: 0.69 (130872 hom.)
• Consequence: MAP4K4 NM_001395002.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.27
• Publications: 6 publications found

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]

MAP4K4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-101697975-T-C is Benign according to our data. Variant chr2-101697975-T-C is described in ClinVar as Benign. ClinVar VariationId is 1259880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395002.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	NM_001395002.1	MANE Select	c.-106T>C		5_prime_UTR	Exon 1 of 33	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.-106T>C		5_prime_UTR	Exon 1 of 32	NP_001371426.1
	MAP4K4	NM_001384492.1		c.-106T>C		5_prime_UTR	Exon 1 of 33	NP_001371421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.-106T>C		5_prime_UTR	Exon 1 of 33	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.-106T>C		5_prime_UTR	Exon 1 of 31	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000902131.1		c.-106T>C		5_prime_UTR	Exon 1 of 31	ENSP00000572190.1

Frequencies

GnomAD3 genomes AF: 0.755 AC: 110693 AN: 146664 Hom.: 42224 Cov.: 33

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.663

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.726

GnomAD4 exome AF: 0.687 AC: 376805 AN: 548186 Hom.: 130872 Cov.: 8 AF XY: 0.688 AC XY: 191972 AN XY: 278996

African (AFR) AF: 0.886 AC: 8951 AN: 10108

American (AMR) AF: 0.704 AC: 9494 AN: 13492

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 5959 AN: 9066

East Asian (EAS) AF: 0.750 AC: 2562 AN: 3414

South Asian (SAS) AF: 0.688 AC: 25048 AN: 36412

European-Finnish (FIN) AF: 0.739 AC: 16033 AN: 21684

Middle Eastern (MID) AF: 0.645 AC: 1547 AN: 2398

European-Non Finnish (NFE) AF: 0.679 AC: 294088 AN: 432832

Other (OTH) AF: 0.699 AC: 13123 AN: 18780

GnomAD4 genome AF: 0.755 AC: 110785 AN: 146758 Hom.: 42272 Cov.: 33 AF XY: 0.757 AC XY: 54092 AN XY: 71410

African (AFR) AF: 0.881 AC: 36172 AN: 41040

American (AMR) AF: 0.717 AC: 10611 AN: 14798

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2268 AN: 3390

East Asian (EAS) AF: 0.785 AC: 3911 AN: 4984

South Asian (SAS) AF: 0.709 AC: 3403 AN: 4798

European-Finnish (FIN) AF: 0.747 AC: 6390 AN: 8556

Middle Eastern (MID) AF: 0.667 AC: 192 AN: 288

European-Non Finnish (NFE) AF: 0.694 AC: 45744 AN: 65960

Other (OTH) AF: 0.728 AC: 1484 AN: 2038

Alfa AF: 0.695 Hom.: 20128

Bravo AF: 0.760

Asia WGS AF: 0.743 AC: 1689 AN: 2272

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.37
PhyloP100		-3.3
PromoterAI		0.058	Neutral
Mutation Taster		=292/8	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13430711; hg19: chr2-102314437;