chr19-12995977-C-T

Variant names:

• chr19-12995977-C-T
• rs189556314
• NM_001365902.3:c.27+113C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001365902.3(NFIX):​c.27+113C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 334,074 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (69 hom., cov: 29)
  • Exomes 𝑓: 0.035 (116 hom.)
• Consequence: NFIX NM_001365902.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.600
• Publications: 4 publications found

Genes affected

NFIX (HGNC:7788): (nuclear factor I X) The protein encoded by this gene is a transcription factor that binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3 in viral and cellular promoters. The encoded protein can also stimulate adenovirus replication in vitro. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

NFIX Gene-Disease associations (from GenCC):

• Malan overgrowth syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, ClinGen, Orphanet
• Marshall-Smith syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-12995977-C-T is Benign according to our data. Variant chr19-12995977-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 677498.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0276 (4095/148622) while in subpopulation NFE AF = 0.0362 (2416/66832). AF 95% confidence interval is 0.0349. There are 69 homozygotes in GnomAd4. There are 1882 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4095 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365902.3. 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
	NFIX	NM_001365902.3	MANE Select	c.27+113C>T		intron	N/A	NP_001352831.1	Q14938-1
	NFIX	NM_002501.4		c.27+113C>T		intron	N/A	NP_002492.2	Q14938-3
	NFIX	NM_001365982.2		c.27+113C>T		intron	N/A	NP_001352911.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	ENST00000592199.6	TSL:5 MANE Select	c.27+113C>T		intron	N/A	ENSP00000467512.1	Q14938-1
	NFIX	ENST00000397661.6	TSL:5	c.27+113C>T		intron	N/A	ENSP00000380781.2	Q14938-3

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4096 AN: 148512 Hom.: 69 Cov.: 29

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.0611

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0396

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00794

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0839

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0416

GnomAD4 exome AF: 0.0350 AC: 6486 AN: 185452 Hom.: 116 AF XY: 0.0358 AC XY: 3155 AN XY: 88214

African (AFR) AF: 0.0202 AC: 68 AN: 3374

American (AMR) AF: 0.0169 AC: 4 AN: 236

Ashkenazi Jewish (ASJ) AF: 0.0439 AC: 51 AN: 1162

East Asian (EAS) AF: 0.00132 AC: 1 AN: 756

South Asian (SAS) AF: 0.00789 AC: 30 AN: 3804

European-Finnish (FIN) AF: 0.0196 AC: 2 AN: 102

Middle Eastern (MID) AF: 0.0603 AC: 24 AN: 398

European-Non Finnish (NFE) AF: 0.0359 AC: 6086 AN: 169620

Other (OTH) AF: 0.0367 AC: 220 AN: 6000

GnomAD4 genome AF: 0.0276 AC: 4095 AN: 148622 Hom.: 69 Cov.: 29 AF XY: 0.0259 AC XY: 1882 AN XY: 72548

African (AFR) AF: 0.0183 AC: 748 AN: 40940

American (AMR) AF: 0.0295 AC: 443 AN: 14992

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 136 AN: 3432

East Asian (EAS) AF: 0.000200 AC: 1 AN: 5012

South Asian (SAS) AF: 0.00794 AC: 38 AN: 4784

European-Finnish (FIN) AF: 0.0159 AC: 149 AN: 9378

Middle Eastern (MID) AF: 0.0839 AC: 24 AN: 286

European-Non Finnish (NFE) AF: 0.0362 AC: 2416 AN: 66832

Other (OTH) AF: 0.0411 AC: 85 AN: 2066

Alfa AF: 0.0293 Hom.: 9

Bravo AF: 0.0289

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		-0.60
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
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: rs189556314; hg19: chr19-13106791;