5-163473189-G-A

Position:

• chr5-163473189-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001142556.2(HMMR):​c.661G>A​(p.Glu221Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,380,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HMMR NM_001142556.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

Genes affected

HMMR (HGNC:5012): (hyaluronan mediated motility receptor) The protein encoded by this gene is involved in cell motility. It is expressed in breast tissue and together with other proteins, it forms a complex with BRCA1 and BRCA2, thus is potentially associated with higher risk of breast cancer. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42073348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMMR	NM_001142556.2	c.661G>A	p.Glu221Lys	missense_variant	8/18	ENST00000393915.9	NP_001136028.1
HMMR	NM_012484.3	c.658G>A	p.Glu220Lys	missense_variant	8/18		NP_036616.2
HMMR	NM_012485.3	c.613G>A	p.Glu205Lys	missense_variant	7/17		NP_036617.2
HMMR	NM_001142557.2	c.400G>A	p.Glu134Lys	missense_variant	5/15		NP_001136029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMMR	ENST00000393915.9	c.661G>A	p.Glu221Lys	missense_variant	8/18	1	NM_001142556.2	ENSP00000377492.4
HMMR	ENST00000358715.3	c.658G>A	p.Glu220Lys	missense_variant	8/18	1		ENSP00000351554.3
HMMR	ENST00000353866.7	c.613G>A	p.Glu205Lys	missense_variant	7/17	1		ENSP00000185942.6
HMMR	ENST00000432118.6	c.400G>A	p.Glu134Lys	missense_variant	5/15	2		ENSP00000402673.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1380452 Hom.: 0 Cov.: 25 AF XY: 0.00000289 AC XY: 2 AN XY: 690994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2024

The c.661G>A (p.E221K) alteration is located in exon 8 (coding exon 8) of the HMMR gene. This alteration results from a G to A substitution at nucleotide position 661, causing the glutamic acid (E) at amino acid position 221 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;.;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.6	.;.;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.84	P;P;P;P
Vest4		0.56
MutPred		0.24		.;.;.;Gain of MoRF binding (P = 0.0081);
MVP		0.84
MPC		0.28
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.21
gMVP		0.41

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-162900195;