rs61730179

Variant names:

• chr4-47848180-T-C
• rs61730179
• NM_001278624.2:c.2719A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001278624.2(NFXL1):​c.2719A>G​(p.Thr907Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,593,056 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: NFXL1 NM_001278624.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.412
• Publications: 2 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028530955).
• BP6: Variant 4-47848180-T-C is Benign according to our data. Variant chr4-47848180-T-C is described in ClinVar as Benign. ClinVar VariationId is 3049869.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00597 (909/152246) while in subpopulation AFR AF = 0.0212 (880/41538). AF 95% confidence interval is 0.02. There are 13 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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.2719A>G	p.Thr907Ala	missense	Exon 23 of 23	NP_001265553.1	Q6ZNB6-1
	NFXL1	NM_001278623.1		c.2719A>G	p.Thr907Ala	missense	Exon 23 of 23	NP_001265552.1	Q6ZNB6-1
	NFXL1	NM_152995.6		c.2719A>G	p.Thr907Ala	missense	Exon 23 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.2719A>G	p.Thr907Ala	missense	Exon 23 of 23	ENSP00000422037.1	Q6ZNB6-1
	NFXL1	ENST00000329043.7	TSL:1	c.2719A>G	p.Thr907Ala	missense	Exon 23 of 23	ENSP00000333113.4	Q6ZNB6-1
	NFXL1	ENST00000464756.6	TSL:1	n.*697A>G		non_coding_transcript_exon	Exon 24 of 24	ENSP00000425812.1	Q6ZNB6-2

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 910 AN: 152128 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00164 AC: 399 AN: 243946 AF XY: 0.00103

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.000795

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000677

GnomAD4 exome AF: 0.000659 AC: 949 AN: 1440810 Hom.: 8 Cov.: 29 AF XY: 0.000586 AC XY: 419 AN XY: 714990

African (AFR) AF: 0.0244 AC: 804 AN: 32954

American (AMR) AF: 0.000887 AC: 38 AN: 42842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.0000364 AC: 3 AN: 82478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52912

Middle Eastern (MID) AF: 0.000876 AC: 5 AN: 5706

European-Non Finnish (NFE) AF: 0.00000909 AC: 10 AN: 1099540

Other (OTH) AF: 0.00150 AC: 89 AN: 59462

GnomAD4 genome AF: 0.00597 AC: 909 AN: 152246 Hom.: 13 Cov.: 32 AF XY: 0.00535 AC XY: 398 AN XY: 74456

African (AFR) AF: 0.0212 AC: 880 AN: 41538

American (AMR) AF: 0.00124 AC: 19 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00225 Hom.: 8

Bravo AF: 0.00668

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NFXL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.52
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.48	N
PhyloP100		0.41
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.015
Sift	Benign	0.55	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.032
MVP		0.22
MPC		0.30
ClinPred		0.00030	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.52
Mutation Taster		=100/0	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

dbSNP: rs61730179; hg19: chr4-47850197; COSMIC: COSV99060895; COSMIC: COSV99060895;