chr13-79481238-G-C

Variant names:

• chr13-79481238-G-C
• rs777025808
• NM_019080.3:c.35G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019080.3(NDFIP2):​c.35G>C​(p.Ser12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,588 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. S12N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NDFIP2 NM_019080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03616759).

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.35G>C	p.Ser12Thr	missense	Exon 1 of 8	NP_061953.2	Q9NV92
	NDFIP2	NM_001394685.1		c.35G>C	p.Ser12Thr	missense	Exon 1 of 8	NP_001381614.1
	NDFIP2	NM_001161407.2		c.35G>C	p.Ser12Thr	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.35G>C	p.Ser12Thr	missense	Exon 1 of 8	ENSP00000218652.7	Q9NV92
	NDFIP2	ENST00000703122.1		c.-248G>C		5_prime_UTR	Exon 1 of 8	ENSP00000515183.1	A0A8V8TQM3
	NDFIP2	ENST00000703126.1		c.-248G>C		5_prime_UTR	Exon 1 of 8	ENSP00000515186.1	A0A8V8TQN2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371588 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 676002

⚠️ 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: 29960

American (AMR) AF: 0.00 AC: 0 AN: 34260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24574

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34622

South Asian (SAS) AF: 0.00 AC: 0 AN: 78152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072992

Other (OTH) AF: 0.00 AC: 0 AN: 57228

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.2
DANN	Benign	0.87
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.20
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.0020
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.23		Gain of catalytic residue at G13 (P = 2e-04)
MVP		0.50
MPC		1.0
ClinPred		0.086	T
GERP RS		-0.91
PromoterAI		-0.029	Neutral
Varity_R		0.049
gMVP		0.11
Mutation Taster		=98/2	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: rs777025808; hg19: chr13-80055373;