13-79481427-T-G

Variant names:

• chr13-79481427-T-G
• rs1594835528
• NM_019080.3:c.224T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019080.3(NDFIP2):​c.224T>G​(p.Val75Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,407,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V75A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NDFIP2 NM_019080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.441
• Publications: 0 publications found

Genes affected

NDFIP2 (HGNC:18537): (Nedd4 family interacting protein 2) Enables WW domain binding activity. Involved in negative regulation of gene expression; negative regulation of transport; and positive regulation of protein ubiquitination. Located in several cellular components, including Golgi apparatus; mitochondrion; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NDFIP2-AS1 (HGNC:40844): (NDFIP2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072942436).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019080.3. 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
	NDFIP2	NM_019080.3	MANE Select	c.224T>G	p.Val75Gly	missense	Exon 1 of 8	NP_061953.2	Q9NV92
	NDFIP2	NM_001394685.1		c.224T>G	p.Val75Gly	missense	Exon 1 of 8	NP_001381614.1
	NDFIP2	NM_001161407.2		c.224T>G	p.Val75Gly	missense	Exon 1 of 8	NP_001154879.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDFIP2	ENST00000218652.12	TSL:1 MANE Select	c.224T>G	p.Val75Gly	missense	Exon 1 of 8	ENSP00000218652.7	Q9NV92
	NDFIP2	ENST00000703122.1		c.-59T>G		5_prime_UTR	Exon 1 of 8	ENSP00000515183.1	A0A8V8TQM3
	NDFIP2	ENST00000703126.1		c.-59T>G		5_prime_UTR	Exon 1 of 8	ENSP00000515186.1	A0A8V8TQN2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1407386 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 694882

⚠️ 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: 32252

American (AMR) AF: 0.00 AC: 0 AN: 36378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 36934

South Asian (SAS) AF: 0.00 AC: 0 AN: 79854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083564

Other (OTH) AF: 0.00 AC: 0 AN: 58324

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.44
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.019
Sift	Benign	0.044	D
Sift4G	Uncertain	0.038	D
Polyphen		0.0	B
Vest4		0.15
MutPred		0.26		Gain of catalytic residue at S70 (P = 0)
MVP		0.093
MPC		1.4
ClinPred		0.036	T
GERP RS		1.5
PromoterAI		0.082	Neutral
Varity_R		0.13
gMVP		0.18
Mutation Taster		=94/6	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: rs1594835528; hg19: chr13-80055562;