chr4-47851140-T-G

Variant names:

• chr4-47851140-T-G
• NM_001278624.2:c.2517A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001278624.2(NFXL1):​c.2517A>C​(p.Glu839Asp) 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. 13/22 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: NFXL1 NM_001278624.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.252
• Publications: 0 publications found

Genes affected

NFXL1 (HGNC:18726): (nuclear transcription factor, X-box binding like 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000282917 (HGNC:58782):

LOC101927179 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30095273).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278624.2. 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
	NFXL1	NM_001278624.2	MANE Select	c.2517A>C	p.Glu839Asp	missense	Exon 22 of 23	NP_001265553.1	Q6ZNB6-1
	NFXL1	NM_001278623.1		c.2517A>C	p.Glu839Asp	missense	Exon 22 of 23	NP_001265552.1	Q6ZNB6-1
	NFXL1	NM_152995.6		c.2517A>C	p.Glu839Asp	missense	Exon 22 of 23	NP_694540.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFXL1	ENST00000507489.2	TSL:1 MANE Select	c.2517A>C	p.Glu839Asp	missense	Exon 22 of 23	ENSP00000422037.1	Q6ZNB6-1
	NFXL1	ENST00000329043.7	TSL:1	c.2517A>C	p.Glu839Asp	missense	Exon 22 of 23	ENSP00000333113.4	Q6ZNB6-1
	NFXL1	ENST00000464756.6	TSL:1	n.*495A>C		non_coding_transcript_exon	Exon 23 of 24	ENSP00000425812.1	Q6ZNB6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	0.014
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.25
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.078
Sift	Benign	0.075	T
Sift4G	Benign	0.10	T
Polyphen		0.91	P
Vest4		0.48
MutPred		0.26		Loss of helix (P = 0.0017)
MVP		0.70
MPC		0.29
ClinPred		0.92	D
GERP RS		2.9
Varity_R		0.17
gMVP		0.48
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

hg19: chr4-47853157;