chr7-73667969-C-T

Variant names:

• chr7-73667969-C-T
• rs1477553464
• NM_001077621.2:c.11C>T

Variant summary

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

The NM_001077621.2(VPS37D):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000078 in 1,063,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: VPS37D NM_001077621.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.104
• Publications: 0 publications found

Genes affected

VPS37D (HGNC:18287): (VPS37D subunit of ESCRT-I) Predicted to be involved in protein targeting to membrane; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway. Located in extracellular exosome. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.029982477).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077621.2. 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
	VPS37D	NM_001077621.2	MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 4	NP_001071089.1	Q86XT2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37D	ENST00000324941.5	TSL:1 MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 4	ENSP00000320416.4	Q86XT2
	VPS37D	ENST00000965880.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 4	ENSP00000635939.1
	VPS37D	ENST00000903466.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 4	ENSP00000573525.1

Frequencies

GnomAD3 genomes AF: 0.0000549 AC: 8 AN: 145820 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000915

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000450 AC: 1 AN: 2220 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000817 AC: 75 AN: 917990 Hom.: 0 Cov.: 28 AF XY: 0.0000856 AC XY: 37 AN XY: 432300

African (AFR) AF: 0.000114 AC: 2 AN: 17486

American (AMR) AF: 0.00 AC: 0 AN: 3356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7370

East Asian (EAS) AF: 0.00 AC: 0 AN: 9140

South Asian (SAS) AF: 0.00 AC: 0 AN: 18570

European-Finnish (FIN) AF: 0.000158 AC: 2 AN: 12682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2116

European-Non Finnish (NFE) AF: 0.0000859 AC: 70 AN: 815218

Other (OTH) AF: 0.0000312 AC: 1 AN: 32052

GnomAD4 genome AF: 0.0000549 AC: 8 AN: 145820 Hom.: 0 Cov.: 30 AF XY: 0.0000564 AC XY: 4 AN XY: 70972

African (AFR) AF: 0.0000249 AC: 1 AN: 40090

American (AMR) AF: 0.0000676 AC: 1 AN: 14798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 4958

South Asian (SAS) AF: 0.00 AC: 0 AN: 4722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000915 AC: 6 AN: 65596

Other (OTH) AF: 0.00 AC: 0 AN: 2022

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.075
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.25	T
Polyphen		0.81	P
Vest4		0.10
MVP		0.043
MPC		1.9
ClinPred		0.19	T
GERP RS		1.7
PromoterAI		-0.19	Neutral
Varity_R		0.19
gMVP		0.33
Mutation Taster		=92/8	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: rs1477553464; hg19: chr7-73082299;