4-163128948-A-G

Variant names:

• chr4-163128948-A-G
• rs763909888
• NM_138386.3:c.1434T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_138386.3(NAF1):​c.1434T>C​(p.Pro478Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P478P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAF1 NM_138386.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0540
• Publications: 0 publications found

Genes affected

NAF1 (HGNC:25126): (nuclear assembly factor 1 ribonucleoprotein) Enables identical protein binding activity and telomerase RNA binding activity. Involved in regulation of nucleobase-containing compound metabolic process; ribosome biogenesis; and telomerase holoenzyme complex assembly. Located in nucleoplasm. Part of sno(s)RNA-containing ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

NAF1 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-163128948-A-G is Benign according to our data. Variant chr4-163128948-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2961812.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.054 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138386.3. 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
	NAF1	NM_138386.3	MANE Select	c.1434T>C	p.Pro478Pro	synonymous	Exon 8 of 8	NP_612395.2	Q96HR8-1
	NAF1	NM_001128931.2		c.1034-1833T>C		intron	N/A	NP_001122403.1	Q96HR8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAF1	ENST00000274054.3	TSL:1 MANE Select	c.1434T>C	p.Pro478Pro	synonymous	Exon 8 of 8	ENSP00000274054.2	Q96HR8-1
	NAF1	ENST00000422287.6	TSL:1	c.1034-1833T>C		intron	N/A	ENSP00000408963.2	Q96HR8-2
	NAF1	ENST00000851282.1		c.1434T>C	p.Pro478Pro	synonymous	Exon 8 of 9	ENSP00000521341.1

Frequencies

GnomAD3 genomes AF: 0.0000244 AC: 1 AN: 40944 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000618

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 1 AN: 701334 Hom.: 0 Cov.: 19 AF XY: 0.00000278 AC XY: 1 AN XY: 359802

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18376

American (AMR) AF: 0.00 AC: 0 AN: 38062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15270

East Asian (EAS) AF: 0.00 AC: 0 AN: 23570

South Asian (SAS) AF: 0.00 AC: 0 AN: 65190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2470

European-Non Finnish (NFE) AF: 0.00000214 AC: 1 AN: 467134

Other (OTH) AF: 0.00 AC: 0 AN: 31014

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000244 AC: 1 AN: 40944 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 19466

African (AFR) AF: 0.00 AC: 0 AN: 10058

American (AMR) AF: 0.00 AC: 0 AN: 2988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1074

East Asian (EAS) AF: 0.000618 AC: 1 AN: 1618

South Asian (SAS) AF: 0.00 AC: 0 AN: 1206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 78

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 20974

Other (OTH) AF: 0.00 AC: 0 AN: 554

Alfa AF: 0.00 Hom.: 0

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	-0.86
CADD	Benign	4.0
DANN	Benign	0.48
PhyloP100		-0.054
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: rs763909888; hg19: chr4-164050100;